Publications by authors named "Qian Zhu"

406 Publications

Performance of noninvasive prenatal screening in twin pregnancies: a retrospective study of 5469 twin pregnancies.

J Matern Fetal Neonatal Med 2021 Apr 1:1-9. Epub 2021 Apr 1.

Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China.

Objectives: To evaluate the performance of noninvasive prenatal screening (NIPS) for the fetal common aneuploidy screening in twin pregnancies.

Methods: The data of 5469 women with twin pregnancies were collected in this retrospective observational study between January 2017 and December 2018. Patients underwent NIPS as first-line screening or after standard serum screening for fetal aneuploidy. The performance of NIPS was examined, and a regression analysis was performed to investigate testing failure in cases of low fetal fraction.

Results: In this study, 2231 (40.8%) patients opted for NIPS as the primary prenatal screening test, and 3238 (59.2%) opted for serum screening, including 440 patients who opted for NIPS after serum screening. Among the 2671 pregnancies with available NIPS outcomes, 11 cases of aneuploidy were identified, seven of trisomy 21 and four of sex chromosome aneuploidy (SCA). The sensitivity and specificity for trisomy 21 were 100% (95% CI, 56.1-100.0%) and 100% (95% CI, 99.8-100.0%), respectively. The positive predictive value (PPV) for SCA was 40.0% (95% CI, 13.7-72.6%). No false negatives were found, with a negative predictive value (NPV) of 100% (95% CI, 99.8-100.0%) in total. In 32 pregnancies who failed NIPS test without available NIPS outcomes due to low fetal fraction, the regression analysis demonstrated that increasing BMI and assisted reproductive technology treatment were significant independent predictors.

Conclusions: NIPS is a high-performing routine primary prenatal screening test in twin pregnancies, with a high PPV and low false positive rate for detecting trisomy 21. It is also useful to identify common sex chromosome aneuploidies in twin pregnancies, with similar performance to that reported in singleton pregnancy.
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http://dx.doi.org/10.1080/14767058.2021.1903860DOI Listing
April 2021

rs4148323 A Allele is Associated With Increased 2-Hydroxy Atorvastatin Formation and Higher Death Risk in Chinese Patients With Coronary Artery Disease.

Front Pharmacol 2021 8;12:586973. Epub 2021 Mar 8.

Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

It is widely accepted that genetic polymorphisms impact atorvastatin (ATV) metabolism, clinical efficacy, and adverse events. The objectives of this study were to identify novel genetic variants influencing ATV metabolism and outcomes in Chinese patients with coronary artery disease (CAD). A total of 1079 CAD patients were enrolled and followed for 5 years. DNA from the blood and human liver tissue samples were genotyped using either Global Screening Array-24 v1.0 BeadChip or HumanOmniZhongHua-8 BeadChip. Concentrations of ATV and its metabolites in plasma and liver samples were determined using a verified ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) method. The patients carrying A allele for the rs4148323 polymorphism () showed an increase in 2-hydroxy ATV/ATV ratio ( = 1.69E-07, false discovery rate [FDR] = 8.66E-03) relative to the value in individuals without the variant allele. The result was further validated by an independent cohort comprising an additional 222 CAD patients ( = 1.08E-07). Moreover, the rs4148323 A allele was associated with an increased risk of death (hazard ratio [HR] 1.774; 95% confidence interval [CI], 1.031-3.052; = 0.0198). In conclusion, our results suggested that the rs4148323 A allele was associated with increased 2-hydroxy ATV formation and was a significant death risk factor in Chinese patients with CAD.
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http://dx.doi.org/10.3389/fphar.2021.586973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982952PMC
March 2021

Analysis of Shoot Architecture Traits in Edamame Reveals Potential Strategies to Improve Harvest Efficiency.

Front Plant Sci 2021 3;12:614926. Epub 2021 Mar 3.

School of Plant and Environmental Sciences, Virginia Tech, Blacksburg, VA, United States.

Edamame is a type of green, vegetable soybean and improving shoot architecture traits for edamame is important for breeding of high-yield varieties by decreasing potential loss due to harvesting. In this study, we use digital imaging technology and computer vision algorithms to characterize major traits of shoot architecture for edamame. Using a population of edamame PIs, we seek to identify underlying genetic control of different shoot architecture traits. We found significant variations in the shoot architecture of the edamame lines including long-skinny and candle stick-like structures. To quantify the similarity and differences of branching patterns between these edamame varieties, we applied a topological measurement called persistent homology. Persistent homology uses algebraic geometry algorithms to measure the structural similarities between complex shapes. We found intriguing relationships between the topological features of branching networks and pod numbers in our plant population, suggesting combination of multiple topological features contribute to the overall pod numbers on a plant. We also identified potential candidate genes including a lateral organ boundary gene family protein and a MADS-box gene that are associated with the pod numbers. This research provides insight into the genetic regulation of shoot architecture traits and can be used to further develop edamame varieties that are better adapted to mechanical harvesting.
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http://dx.doi.org/10.3389/fpls.2021.614926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965963PMC
March 2021

Author Correction: Transcription factor competition at the γ-globin promoters controls hemoglobin switching.

Nat Genet 2021 Apr;53(4):586

Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41588-021-00834-xDOI Listing
April 2021

RNF8-ubiquitinated KMT5A is required for RNF168-induced H2A ubiquitination in response to DNA damage.

FASEB J 2021 Apr;35(4):e21326

Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, China.

Histone modifications play critical roles in DNA damage repair to safeguard genome integrity. However, how different histone modifiers coordinate to build appropriate chromatin context for DNA damage repair is largely unknown. Here, we report a novel interplay between the histone methyltransferase KMT5A and two E3 ligases RNF8 and RNF168 in establishing the histone modification status for DNA damage repair. KMT5A is a newly identified substrate of RNF8 in vitro and in vivo. In response to DNA double-strand breaks (DSBs), RNF8 promotes KMT5A recruitment onto damaged chromatin in a ubiquitination-dependent manner. RNF8-induced KMT5A ubiquitination increases the binding capacity of KMT5A to RNF168. Interestingly, KMT5A not only drives a local increase in H4K20 monomethylation at DSBs, but also promotes RNF168's activity in catalyzing H2A ubiquitination. We proved that the interaction between the H2A acidic patch and KMT5A R188/R189 residues is critical for KMT5A-mediated regulation of H2A ubiquitination. Taken together, our results highlight a new role for KMT5A in linking H4K20 methylation and H2A ubiquitination and provide insight into the histone modification network during DNA damage repair.
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http://dx.doi.org/10.1096/fj.202002234RDOI Listing
April 2021

Application of deep learning to predict underestimation in ductal carcinoma in situ of the breast with ultrasound.

Ann Transl Med 2021 Feb;9(4):295

CAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China.

Background: To develop an ultrasound-based deep learning model to predict postoperative upgrading of pure ductal carcinoma in situ (DCIS) diagnosed by core needle biopsy (CNB) before surgery.

Methods: Of the 360 patients with DCIS diagnosed by CNB and identified retrospectively, 180 had lesions upstaged to ductal carcinoma in situ with microinvasion (DCISM) or invasive ductal carcinoma (IDC) postoperatively. Ultrasound images obtained from the hospital database were divided into a training set (n=240) and validation set (n=120), with a ratio of 2:1 in chronological order. Four deep learning models, based on the ResNet and VggNet structures, were established to classify the ultrasound images into postoperative upgrade and pure DCIS. We obtained the area under the receiver operating characteristic curve (AUROC), specificity, sensitivity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) to estimate the performance of the predictive models. The robustness of the models was evaluated by a 3-fold cross-validation.

Results: Clinical features were not significantly different between the training set and the test set (P value >0.05). The area under the receiver operating characteristic curve of our models ranged from 0.724 to 0.804. The sensitivity, specificity, and accuracy of the optimal model were 0.733, 0.750, and 0.742, respectively. The three-fold cross-validation results showed that the model was very robust.

Conclusions: The ultrasound-based deep learning prediction model is effective in predicting DCIS that will be upgraded postoperatively.
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http://dx.doi.org/10.21037/atm-20-3981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944276PMC
February 2021

DOCK7 protects against replication stress by promoting RPA stability on chromatin.

Nucleic Acids Res 2021 Apr;49(6):3322-3337

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.

RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer.
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http://dx.doi.org/10.1093/nar/gkab134DOI Listing
April 2021

Giotto: a toolbox for integrative analysis and visualization of spatial expression data.

Genome Biol 2021 Mar 8;22(1):78. Epub 2021 Mar 8.

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Spatial transcriptomic and proteomic technologies have provided new opportunities to investigate cells in their native microenvironment. Here we present Giotto, a comprehensive and open-source toolbox for spatial data analysis and visualization. The analysis module provides end-to-end analysis by implementing a wide range of algorithms for characterizing tissue composition, spatial expression patterns, and cellular interactions. Furthermore, single-cell RNAseq data can be integrated for spatial cell-type enrichment analysis. The visualization module allows users to interactively visualize analysis outputs and imaging features. To demonstrate its general applicability, we apply Giotto to a wide range of datasets encompassing diverse technologies and platforms.
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http://dx.doi.org/10.1186/s13059-021-02286-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938609PMC
March 2021

Analysis of Synthetic Monodisperse Polysaccharides by Wide Mass Range Ultrahigh-Resolution MALDI Mass Spectrometry.

Anal Chem 2021 03 5;93(10):4666-4675. Epub 2021 Mar 5.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.

Carbohydrates, such as oligo- and polysaccharides, are highly abundant biopolymers that are involved in numerous processes. The study of their structure and functions is commonly based on a material that is isolated from complex natural sources. However, a more precise analysis requires pure compounds with well-defined structures that can be obtained from chemical or enzymatic syntheses. Novel synthetic strategies have increased the accessibility of larger monodisperse polysaccharides, posing a challenge to the analytical methods used for their molecular characterization. Here, we present wide mass range ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) as a powerful platform for the analysis of synthetic oligo- and polysaccharides. Synthetic carbohydrates 16-, 64-, 100-, and 151-mers were mass analyzed and characterized by MALDI in-source decay FT-ICR MS. Detection of fragment ions generated from glycosidic bond cleavage (or cross-ring cleavage) provided information of the monosaccharide content and the linkage type, allowing for the corroboration of the carbohydrate compositions and structures.
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http://dx.doi.org/10.1021/acs.analchem.1c00239DOI Listing
March 2021

Transcription factor competition at the γ-globin promoters controls hemoglobin switching.

Nat Genet 2021 Apr 1;53(4):511-520. Epub 2021 Mar 1.

Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

BCL11A, the major regulator of fetal hemoglobin (HbF, αγ) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult hemoglobin (HbA, αβ). To uncover how BCL11A initiates repression, we used CRISPR-Cas9, dCas9, dCas9-KRAB and dCas9-VP64 screens to dissect the γ-globin promoters and identified an activator element near the BCL11A-binding site. Using CUT&RUN and base editing, we demonstrate that a proximal CCAAT box is occupied by the activator NF-Y. BCL11A competes with NF-Y binding through steric hindrance to initiate repression. Occupancy of NF-Y is rapidly established following BCL11A depletion, and precedes γ-globin derepression and locus control region (LCR)-globin loop formation. Our findings reveal that the switch from fetal to adult globin gene expression within the >50-kb β-globin gene cluster is initiated by competition between a stage-selective repressor and a ubiquitous activating factor within a remarkably discrete region of the γ-globin promoters.
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http://dx.doi.org/10.1038/s41588-021-00798-yDOI Listing
April 2021

Inhibition of ATM induces hypersensitivity to proton irradiation by upregulating toxic end joining.

Cancer Res 2021 Feb 17. Epub 2021 Feb 17.

Radiation Oncology, Mayo Clinic

Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here we performed genetic or pharmacologic manipulation of key DNA damage response elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double strand breaks induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ATM inhibitor AZD0156 but not an inhibitor of ATR rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more double strand breaks to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor co-administration showed enhanced efficacy in HR proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR proficient tumors selectively enhance the relative biological effectiveness of proton Bragg peak irradiation.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2960DOI Listing
February 2021

A Soft Pressure Sensor Skin to Predict Contact Pressure Limit Under Hand Orthosis.

IEEE Trans Neural Syst Rehabil Eng 2021 3;29:536-545. Epub 2021 Mar 3.

Customized static orthoses in rehabilitation clinics often cause side effects, such as discomfort and skin damage due to excessive local contact pressure. Currently, clinicians adjust orthoses to reduce high contact pressure based on subjective feedback from patients. However, the adjustment is inefficient and prone to variability due to the unknown contact pressure distribution as well as differences in discomfort due to pressure across patients. This paper proposed a new method to predict a threshold of contact pressure (pressure limit) associated with moderate discomfort at each critical spot under hand orthoses. A new pressure sensor skin with 13 sensing units was configured from FEA results of pressure distribution simulated with hand geometry data of six healthy participants. It was used to measure contact pressure under two types of customized orthoses for 40 patients with bone fractures. Their subjective perception of discomfort was also measured using a 6 scores discomfort scale. Based on these data, five critical spots were identified that correspond to high discomfort scores (>1) or high pressure magnitudes (>0.024 MPa). An artificial neural network was trained to predict contact pressure at each critical spot with orthosis type, gender, height, weight, discomfort scores and pressure measurements as input variables. The neural networks show satisfactory prediction accuracy with R values over 0.81 of regression between network outputs and measurements. This new method predicts a set of pressure limits at critical locations under the orthosis that the clinicians can use to make orthosis adjustment decisions.
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http://dx.doi.org/10.1109/TNSRE.2021.3059015DOI Listing
March 2021

Mitochondrial uncoupling protein 2 is regulated through heterogeneous nuclear ribonucleoprotein K in lead exposure models.

J Environ Sci Health C Toxicol Carcinog 2021 ;39(1):1-16

Department of Histology and Embryology, School of Medicine, Nanchang University, Nanchang, P.R. China.

Synaptic plasticity plays an important role in learning and memory in the developing hippocampus. However, the precise molecular mechanism in lead exposure models remains to be studied. UCP2, an inner mitochondrial anion carrier, regulates synaptic plasticity through uncoupling neurons. And hnRNP K, an RNA binding protein, plays a role in modulating the expression of transcripts coding synaptic plasticity. We aim to investigate whether lead exposure affects UCP2 and hnRNP K expression levels. The Sprague-Dawley rats were exposed to different lead acetate concentrations (0 g/l, 0.5 g/l, 2.0 g/l) during gestational and lactational periods. PC12 cells were also exposed to different lead acetate concentrations (0 μM, 1 μM and 100 μM). We found that the expression levels of UCP2 and hnRNP K had significant declines in the lead exposure rat hippocampus and PC12 cells. Furthermore, the up-regulation of hnRNP K expression level could reverse the expression level of UCP2 in lead exposure models. In conclusion, these results suggest that lead exposure can reduce the expression level of UCP2 which is mediated by decreasing the expression level of hnRNP K.
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http://dx.doi.org/10.1080/26896583.2020.1854596DOI Listing
January 2021

Structural and Functional Changes in the Cerebellum and Brainstem in Patients with Benign Paroxysmal Positional Vertigo.

Cerebellum 2021 Feb 6. Epub 2021 Feb 6.

Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, 200062, China.

Benign paroxysmal positional vertigo (BPPV) is one of the most common peripheral vestibular diseases. Since the peripheral vestibular system connects with the cerebellum via the brainstem, repeated episodic vertigo may result in progressive structural and functional changes in the cerebellum and brainstem. In the present work, voxel-based morphometry (VBM) of T1-weighted images and resting-state functional magnetic resonance imaging (fMRI) in 32 patients with BPPV and 32 matched healthy controls were used to assess cerebellar and brainstem anatomical and spontaneous resting-state brain activity alterations associated with BPPV. We used a spatially unbiased infratentorial template toolbox in combination with VBM to analyze cerebellar and brainstem gray matter volume (GMV), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo). Patients with BPPV showed decreased GMV in the right cerebellum posterior lobe/cerebellar tonsil extending to the cerebellum anterior lobe and pons relative to healthy controls. BPPV patients also exhibited significantly higher fALFF values in the right pons and left pons and higher ReHo values in the left cerebellum posterior lobe/Crus2 than the controls. Furthermore, the fALFF z-scores in the pons were positively correlated with the duration of vertigo at baseline and dizziness visual analog scale scores 1 week after canalith repositioning procedures (CRPs). BPPV patients exhibited structural and functional changes in the cerebellum and pons, which may reflect the adaptation and plasticity of these anatomical structures after repeated attacks of episodic vertigo. These results indicate that the changes in pons function may be closely related to residual dizziness after CRPs.
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http://dx.doi.org/10.1007/s12311-021-01237-8DOI Listing
February 2021

Simultaneous heavy metal removal and sludge deep dewatering with Fe(II) assisted electrooxidation technology.

J Hazard Mater 2021 Mar 9;405:124072. Epub 2020 Oct 9.

School of Environmental Science and Engineering, Huazhong University of Science and Technology (HUST), Wuhan 430074, PR China; Hubei Provincial Engineering Laboratory of Solid Waste Treatment, Disposal and Recycle Technology, Wuhan 430074, PR China. Electronic address:

A hybrid sludge conditioning strategy with electrooxidation and Fe(II) addition was used for heavy metal removal from sewage sludge and industrial sludge, with simultaneous sludge dewatering and stabilization. With the addition of 82 mg/g DS Fe(II) and treatment time of 4.5 h, heavy metal removals of 72.95% and 78.49% for Cu, 66.29% and 84.26% for Zn, and 36.52% and 36.99% for Pb were achieved from sewage sludge and industrial sludge samples respectively. The system pH decreased to 2.33 and 2.98 and the oxidation-reduction potential (ORP) values increased to 435.90 mV and 480.60 mV in sewage sludge and industrial sludge samples, respectively, which was conducive to the desorption and dissolution of heavy metals from sludge structures and the degradation of the organic compounds that complexed with heavy metals. In addition, the hybrid conditioning process demonstrated excellent dewatering performance due to the efficient electrochemical disintegration of sludge flocs together with the coagulation of sludge particles by Fe(III) generated via electrooxidation. The strong acidic and oxidative environment produced by the enhanced electrooxidation process was also responsible for pathogen inactivation.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124072DOI Listing
March 2021

Recent insights into the impact of immune dysfunction on reproduction in autoimmune thyroiditis.

Clin Immunol 2021 Mar 2;224:108663. Epub 2021 Jan 2.

Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. Electronic address:

Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease with a high incidence among women of childbearing age. Recent studies have reported that women with AIT are more susceptible to infertility, miscarriage and preterm birth. It has been investigated that abnormal changes in maternal immune system and maternal-fetal interface can dampen the immune tolerance between mother and fetus, which underlie the pathogenesis of adverse pregnancy outcomes. Hence, we summarize the immunological changes related to adverse reproductive outcomes in AIT and highlight the respective contributions of both humoral and cellular immune dysfunctions to pregnancy failures. Moreover, the direct impacts of AIT on maternal-fetal immune activation and biological influences to trophoblasts are discussed as well. All these associations require confirmation in larger studies, and the pathogenic mechanisms need to be better understood, which might provide useful information for clinical diagnosis and therapy of AIT.
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http://dx.doi.org/10.1016/j.clim.2020.108663DOI Listing
March 2021

Dietary Probiotics or Synbiotics Supplementation During Gestation, Lactation, and Nursery Periods Modifies Colonic Microbiota, Antioxidant Capacity, and Immune Function in Weaned Piglets.

Front Vet Sci 2020 14;7:597832. Epub 2020 Dec 14.

Department of Food Science and Engineering, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, China.

This study was conducted to investigate the effect of dietary probiotics or synbiotics supplementation on colonic microbiota, antioxidant capacity, and immune function in weaned piglets. A total of 64 pregnant Bama mini-sows and then 128 of their weaned piglets were randomly assigned into control group, antibiotics group, probiotics group, or synbiotics group. The results showed that colonic and abundances in the probiotics group and total bacteria, , and abundances in the synbiotics group were increased ( < 0.05), while abundance in the synbiotics group was decreased ( = 0.061) compared with the control group. , and total bacteria abundances were increased ( < 0.05) in the probiotics and synbiotics groups compared with the antibiotics group. Probiotics supplementation up-regulated ( < 0.05) the mRNA expression of GPR109A compared with the control and antibiotics groups. Dietary probiotics or synbiotics supplementation improved the antioxidant capacity by increasing ( < 0.05) the colonic CAT, GSH-Px, SOD, and T-AOC levels and plasma CAT, GSH, GSH-Px, and SOD levels and by decreasing ( < 0.05) the colonic and plasma MDA and HO levels. Compared to the control group, the colonic IL-10, IFN-α, and sIgA concentrations and plasma IgA and IgM concentrations were significantly increased ( < 0.05) in the probiotics and synbiotics groups. Spearman's correlation analysis showed that the changed colonic microbiota, such as and were correlated with the alteration of antioxidant indexes, cytokines, and immunoglobulins. In conclusion, dietary probiotics or synbiotics supplementation during gestation, lactation, and nursery periods could be used as an alternative for antibiotics in terms of gut health of weaned piglets.
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http://dx.doi.org/10.3389/fvets.2020.597832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767837PMC
December 2020

Supplementing Synbiotic in Sows' Diets Modifies Beneficially Blood Parameters and Colonic Microbiota Composition and Metabolic Activity in Suckling Piglets.

Front Vet Sci 2020 30;7:575685. Epub 2020 Nov 30.

CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China.

Nutrients in the maternal diet favor the growth and development of suckling piglets and alter their gut microbiota composition and metabolic activity, thus affecting the hosts. The present study analyzed, in suckling piglets from sows receiving antibiotic or synbiotic supplements from pregnancy to lactation, several biochemical parameters, oxidative/anti-oxidative indices, inflammatory cytokines, and ingestion-related factor levels in plasma, as well as colonic microbiota composition and metabolic activity, and mucosal expression of genes related to the intestinal barrier function. Compared with the control group, maternal synbiotic supplementation decreased ( < 0.05) the plasma levels of glucose, AMM, TC, low-density lipoprotein-cholesterol (LDL-C), MDA, HO, ghrelin, CCK, PP, IL-1β, IL-2, IL-6, TNF-α, Ala, Cys, Tau, and β-AiBA, the levels of propionate and total short-chain fatty acids (SCFAs) in the colonic luminal content, and colonic abundances of , and ; while increased ( < 0.05) the plasma levels of urea nitrogen (UN), Ile, Leu, α-AAA, α-ABA, and 1-Mehis, as well as colonic abundances of , and . Compared with the antibiotic group, maternal synbiotic supplementation decreased ( < 0.05) the plasma levels of glucose, gastrin, and Ala, as well as abundances of and and propionate level in the colonic content. Expression of genes coding for E-cadherin, Occludin, ZO-1, ZO-2, IL-10, and interferon-α were down-regulated in the colonic mucosa. The synbiotic supplementation increased ( < 0.05) the plasma levels of UN, Leu, α-ABA, and 1-Mehis, the abundances of , and and expression of genes coding for E-cadherin, Occludin, ZO-1, ZO-2, IL-10, and interferon-α. Spearman correlation analysis showed that there was a positive correlation between colonic abundance and acetate and SCFAs levels; whereas a negative correlation between and abundances and acetate level. These findings suggest that synbiotic supplementation in the maternal diet improved nutrient metabolism and intestinal barrier permeability, reduced oxidative stress, and modified colonic microbiota composition and metabolic activity in suckling piglets.
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http://dx.doi.org/10.3389/fvets.2020.575685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734190PMC
November 2020

The impact of early discontinuation/dose modification of venetoclax on outcomes in patients with relapsed/refractory chronic lymphocytic leukemia: post-hoc analyses from the phase III MURANO study.

Haematologica 2020 12 17;Online ahead of print. Epub 2020 Dec 17.

Peter MacCallum Cancer Centre, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC.

Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We present data from the phase III MURANO study on the impact of venetoclax modification or premature discontinuation on outcomes in patients with R/R CLL. Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinuation/modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140/194 (72%) patients in the VenR arm completed 2 years of therapy; 54/194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing venetoclax for any reason (disease progression excluded; p.
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http://dx.doi.org/10.3324/haematol.2020.266486DOI Listing
December 2020

Prediction of Sentinel Lymph Node Metastasis in Breast Ductal Carcinoma Diagnosed by Preoperative Core Needle Biopsy.

Front Oncol 2020 10;10:590686. Epub 2020 Nov 10.

Department of Medical Ultrasound, Fudan University Shanghai Cancer Center, Shanghai, China.

Purpose: The positivity of sentinel lymph node (SLN) metastasis is relatively low in ductal carcinoma (DCIS) patients. The aim of this study was to investigate factors associated with SLN metastasis and build a model to predict the potential risk of SLN metastasis in patients with a preoperative diagnosis of DCIS.

Patients And Methods: Core needle biopsy-proved DCIS patients who underwent SLN biopsy and breast surgery were retrospectively reviewed and selected. Univariate analysis was used to identify the variables correlated with SLN metastasis. A model to predict SLN metastasis was developed using a multivariate logistic regression in the training set and then validated in an internal set.

Results: A total of 407 patients with a preoperative diagnosis of DCIS were included. Upstaging to invasive/microinvasive cancer occurred in 225 patients after surgery. SLN metastasis was found in 42 patients, including 32 patients upstaging to invasive disease, 8 to microinvasive disease, and 2 pure DCIS. Tumor size based on US examination, axillary ultrasound finding, multifocality, surgery, upstaging, and Ki-67 expression were significantly related to SLN metastasis. The model incorporating tumor size, axillary ultrasound finding and multifocality yielded an AUC of 0.805 (95% CI: 0.715-0.895, <0.001) in the training set, and 0.729 (95% CI: 0.547-0.911, =0.013) in the testing set.

Conclusion: A simple model was developed to predict SLN metastasis in patients with a preoperative diagnosis of DCIS. With good discriminatory power, this model should be helpful for surgeons to decide if SLN biopsy could be safely avoided in certain patients.
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http://dx.doi.org/10.3389/fonc.2020.590686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693536PMC
November 2020

A split aptamer (SPA)-based sandwich-type biosensor for facile and rapid detection of streptomycin.

J Hazard Mater 2021 02 13;403:123941. Epub 2020 Sep 13.

State Key Joint Laboratory of ESPC, School of Environment, Tsinghua University, Beijing, 100084, China; National Engineering Laboratory for Advanced Technology and Equipment of Water Environment Pollution Monitoring, Changsha, 410205, China. Electronic address:

As antibiotic pollution is gaining prominence as a global issue, the demand for detection of streptomycin (STR), which is a widely used antibiotic with potential human health and ecological risks, has attracted increasing attention. Aptamer-based biosensors have been developed for the detection of STR in buffers and samples, however, the non-target signals due to the conformational variation of free aptamers possibly affect their sensitivity and stability. In this study, by introducing the STR-specific split aptamer (SPA), a sensitive evanescent wave fluorescent (EWF) biosensor is developed for the sandwich-type based detection of STR. The standard calibration curve obtained for STR has a detection limit of 33 nM with a linear range of 60-526 nM. This biosensor exhibited good selectivity, reliable reusability for at least 100 times measurements, and high recovery rates for spiked water samples; moreover, all detection steps are easy-to-operate and can be completed in 5 min. Therefore, it exhibits great promise for actual on-site environmental monitoring. Additionally, without introducing any other oligonucleotides or auxiliary materials, this SPA-based biosensing method shows potential as a simple, sensitive, and low-cost manner for the detection of other small molecular targets.
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http://dx.doi.org/10.1016/j.jhazmat.2020.123941DOI Listing
February 2021

The deubiquitinase USP36 Regulates DNA replication stress and confers therapeutic resistance through PrimPol stabilization.

Nucleic Acids Res 2020 12;48(22):12711-12726

Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.

PrimPol has been recently identified as a DNA damage tolerant polymerase that plays an important role in replication stress response. However, the regulatory mechanisms of PrimPol are not well defined. In this study, we identify that the deubiquitinase USP36 interferes with degradation of PrimPol to regulate the replication stress response. Mechanistically, USP36 is deubiquitinated following DNA replication stress, which in turn facilitates its upregulation and interaction with PrimPol. USP36 deubiquitinates K29-linked polyubiquitination of PrimPol and increases its protein stability. Depletion of USP36 results in replication stress-related defects and elevates cell sensitivity to DNA-damage agents, such as cisplatin and olaparib. Moreover, USP36 expression positively correlates with the level of PrimPol protein and poor prognosis in patient samples. These findings indicate that the regulation of PrimPol K29-linked ubiquitination by USP36 plays a critical role in DNA replication stress and chemotherapy response.
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http://dx.doi.org/10.1093/nar/gkaa1090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736794PMC
December 2020

Molecular characteristics of H9N2 influenza viruses isolated from farmed raccoon dogs and arctic foxes in China.

Res Vet Sci 2021 Mar 14;135:542-546. Epub 2020 Nov 14.

Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong Province, 271018, China; College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong Province 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong Province 271018, China. Electronic address:

In this study, eight H9N2 IAVs were isolated from infected diseased, farmed raccoon dogs and arctic foxes. Eight genes shared 98.6%-100% identity among the isolates possessing a PSRSSR/GL motif at the HA cleavage site, which is same as the motif of G1 and Y280 lineages of H9N2 IAVs. The phylogenetic analysis showed that the HA genes of the eight isolates clustered with Y280-like viruses, whereas the NA genes belonged to F/98-like sublineage. Interestingly, the NS, NP, PB2 and PA genes of the isolates were closely related to H7N9 IAVs. This is the first evidence for isolation of H9N2 IAVs from raccoon dogs and arctic foxes. Raccoon dogs and arctic foxes potentially serve as an intermediate host for influenza viruses with pandemic potential toward other animals due to co-expression of both SA α-2,6-Gal and SA α-2,3-Gal receptors in a wide range of their tissues.
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http://dx.doi.org/10.1016/j.rvsc.2020.11.006DOI Listing
March 2021

Annexin A3 upregulates the infiltrated neutrophil-lymphocyte ratio to remodel the immune microenvironment in hepatocellular carcinoma.

Int Immunopharmacol 2020 Dec 13;89(Pt A):107139. Epub 2020 Nov 13.

State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine; Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, PR China. Electronic address:

Accumulating evidence has indicated that inflammation is required for the initiation and progression of hepatocellular carcinoma (HCC). The annexin family protein, which has a highly similar structure, has been demonstrated to participate in pro- or anti-inflammatory regulation in the developing of tumours. However, the potential effects of ANXA3 in the immune microenvironment of HCC remain unknown. In present study, we found that increased ANXA3 expression is associated with a higher infiltrated neutrophil-lymphocyte ratio (iNLR) in HCC. Moreover, HCC patients with a high iNLR and high ANXA3 expression confer the highest risk of death. ANXA3 can be detected in both cell lysates and culture supernatants. However, the secretory ANXA3 did not directly regulate the iNLR. Further study demonstrated that ANXA3 upregulated the iNLR by inducing chemokine CXCL8 and CCL25 release from HCC cells. We further confirmed that ANXA3 promotes tumourigenesis and detected the same associations between ANXA3 and the iNLR or chemokines in vivo. Our findings indicate that ANXA3 regulates the chemokine to remodel the iNLR and promotes tumourigenicity in HCC. These results further expanded our understanding of ANXA3 in the microenvironment of HCC and might provide novel targets for the investigation of molecular treatments for HCC patients.
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http://dx.doi.org/10.1016/j.intimp.2020.107139DOI Listing
December 2020

An integrative knowledge graph for rare diseases, derived from the Genetic and Rare Diseases Information Center (GARD).

J Biomed Semantics 2020 11 12;11(1):13. Epub 2020 Nov 12.

Office of Rare Disease Research, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.

Background: The Genetic and Rare Diseases (GARD) Information Center was established by the National Institutes of Health (NIH) to provide freely accessible consumer health information on over 6500 genetic and rare diseases. As the cumulative scientific understanding and underlying evidence for these diseases have expanded over time, existing practices to generate knowledge from these publications and resources have not been able to keep pace. Through determining the applicability of computational approaches to enhance or replace manual curation tasks, we aim to both improve the sustainability and relevance of consumer health information, but also to develop a foundational database, from which translational science researchers may start to unravel disease characteristics that are vital to the research process.

Results: We developed a meta-ontology based integrative knowledge graph for rare diseases in Neo4j. This integrative knowledge graph includes a total of 3,819,623 nodes and 84,223,681 relations from 34 different biomedical data resources, including curated drug and rare disease associations. Semi-automatic mappings were generated for 2154 unique FDA orphan designations to 776 unique GARD diseases, and 3322 unique FDA designated drugs to UNII, as well as 180,363 associations between drug and indication from Inxight Drugs, which were integrated into the knowledge graph. We conducted four case studies to demonstrate the capabilities of this integrative knowledge graph in accelerating the curation of scientific understanding on rare diseases through the generation of disease mappings/profiles and pathogenesis associations.

Conclusions: By integrating well-established database resources, we developed an integrative knowledge graph containing a large volume of biomedical and research data. Demonstration of several immediate use cases and limitations of this process reveal both the potential feasibility and barriers of utilizing graph-based resources and approaches to support their use by providers of consumer health information, such as GARD, that may struggle with the needs of maintaining knowledge reliant on an evolving and growing evidence-base. Finally, the successful integration of these datasets into a freely accessible knowledge graph highlights an opportunity to take a translational science view on the field of rare diseases by enabling researchers to identify disease characteristics, which may play a role in the translation of discover across different research domains.
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http://dx.doi.org/10.1186/s13326-020-00232-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663894PMC
November 2020

HLA-A and HLA-DRB1 may play a unique role in ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis.

Reprod Biol Endocrinol 2020 Nov 7;18(1):107. Epub 2020 Nov 7.

Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, No. 910, Hengshan Rd, Shanghai, 200030, China.

Background: Ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) is a severe autoimmune neurological disorder, and the influence of teratoma-induced autoantibodies on the pathogenesis remains unclear.

Methods: Ovarian teratoma tissues were collected from teratoma patients with and without NMDAR-E. Proteins were extracted and then analyzed using iTRAQ-coupled LC-MS/MS, which was followed by bioinformatics analysis. Candidate proteins were verified by Western blotting and immunohistochemistry.

Results: In total, 36 differentially expressed proteins (DEPs) were identified between the control group and NMDAR-E group, and the bioinformatics analysis revealed that the DEPs were mainly involved in immune-related pathways, especially HLA-A and HLA-DRB1. The western blotting results for HLA-A and HLA-DRB1 were consistent with the results of the iTRAQ analysis. Additionally, the immunohistochemical data revealed that the aggregation of HLA-A (+) and HLA-DRB1 (+) cells was more apparent in the teratoma tissues of NMDAR-E patients compared with that in the tissues of controls.

Conclusion: Our investigation indicated that HLA-A and HLA-DRB1 might be involved in mediating ovarian teratoma-associated NMDAR-E. These findings provide new insights into the pathophysiological mechanisms and provide information for the functional exploration of proteins in the future.
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http://dx.doi.org/10.1186/s12958-020-00661-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648266PMC
November 2020

Leveraging the UMLS As a Data Standard for Rare Disease Data Normalization and Harmonization.

Methods Inf Med 2020 08 4;59(4-05):131-139. Epub 2020 Nov 4.

Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland, United States.

Objective: In this study, we aimed to evaluate the capability of the Unified Medical Language System (UMLS) as one data standard to support data normalization and harmonization of datasets that have been developed for rare diseases. Through analysis of data mappings between multiple rare disease resources and the UMLS, we propose suggested extensions of the UMLS that will enable its adoption as a global standard in rare disease.

Methods: We analyzed data mappings between the UMLS and existing datasets on over 7,000 rare diseases that were retrieved from four publicly accessible resources: Genetic And Rare Diseases Information Center (GARD), Orphanet, Online Mendelian Inheritance in Men (OMIM), and the Monarch Disease Ontology (MONDO). Two types of disease mappings were assessed, (1) curated mappings extracted from those four resources; and (2) established mappings generated by querying the rare disease-based integrative knowledge graph developed in the previous study.

Results: We found that 100% of OMIM concepts, and over 50% of concepts from GARD, MONDO, and Orphanet were normalized by the UMLS and accurately categorized into the appropriate UMLS semantic groups. We analyzed 58,636 UMLS mappings, which resulted in 3,876 UMLS concepts across these resources. Manual evaluation of a random set of 500 UMLS mappings demonstrated a high level of accuracy (99%) of developing those mappings, which consisted of 414 mappings of synonyms (82.8%), 76 are subtypes (15.2%), and five are siblings (1%).

Conclusion: The mapping results illustrated in this study that the UMLS was able to accurately represent rare disease concepts, and their associated information, such as genes and phenotypes, and can effectively be used to support data harmonization across existing resources developed on collecting rare disease data. We recommend the adoption of the UMLS as a data standard for rare disease to enable the existing rare disease datasets to support future applications in a clinical and community settings.
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http://dx.doi.org/10.1055/s-0040-1718940DOI Listing
August 2020

Effects of oil-soluble versus water-soluble contrast media at hysterosalpingography on pregnancy outcomes in women with a low risk of tubal disease: study protocol for a randomised controlled trial.

BMJ Open 2020 10 27;10(10):e039166. Epub 2020 Oct 27.

Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Introduction: In recent years, due to various factors, the rate of infertility in China has increased and now affects over 10% of women of reproductive age. Hysterosalpingography (HSG) is a common diagnostic procedure during fertility examinations. However, there is no consensus on the choice of contrast agents and their effects. As the largest multicentre, randomised controlled trial (H2Oil trial from the Netherlands) has shown that oil-soluble contrast at HSG can enhance fertility compared with water-soluble contrast, we propose this study to examine whether the use of oil-soluble contrast media results in increased rates of pregnancy in Chinese women undergoing HSG.

Methods And Analysis: This study is a single-centre, randomised, controlled, parallel-group, superiority trial. Patients with low risk of tubal disease will be randomised to undergo HSG using iodinated oil injection (OSCM group, oil-soluble contrast media) or ioversol injection (WSCM group, water-soluble contrast media). To evaluate the potential superiority of the OSCM group, with 1:1 allocation ratio, 90% statistical power and a two-sided significance level of 5%, we have calculated a sample of 520 women per group to be enrolled, for a total of 1040 including 10% loss to follow-up or protocol variation. The primary outcome is the rate of ongoing pregnancy during 6 months after randomisation. The secondary outcomes will consist of thyroid function of patients and newborns, pain scores during HSG, rate of live birth, clinical pregnancies, miscarriages, ectopic pregnancy, time to ongoing pregnancy, time to live birth, cost calculations of the OSCM group/WSCM group, and assisted reproductive technology treatments between the two groups.

Ethics And Dissemination: This protocol received authorisation from the Medical Research Ethics Committee of International Peace Maternity and Child Health Hospital on 18 January 2020 (approval no GKLW2020-02). The findings will be reported in peer-reviewed publications and presentations at international scientific meetings.

Trial Registration Number: ChiCTR2000031612.
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http://dx.doi.org/10.1136/bmjopen-2020-039166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597517PMC
October 2020