Publications by authors named "Ting Bai"

58 Publications

Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis.

Sci Transl Med 2021 Oct 6;13(614):eabd1206. Epub 2021 Oct 6.

Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.

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http://dx.doi.org/10.1126/scitranslmed.abd1206DOI Listing
October 2021

Construction and Evaluation of a Rat Model of Postpartum Fatigue.

Gynecol Obstet Invest 2021 27;86(4):370-378. Epub 2021 Aug 27.

Nursing Research Institute of Affiliated Hospital of Nantong University, Nantong, China.

Objectives: The aim of the study was to construct and evaluate a rat model of postpartum fatigue.

Design: This is an article about animal model building.

Methods: Sprague-Dawley rats on the 1st day after delivery were randomized into control group and fatigue group. The deep sleep of rats was interfered with by forcing them to stand in water, to make the rats experience mental and physical fatigue. To maintain galactosis and lactation, rats and pups were caged for 90 min after every 3 h of separation. The control group was separated routinely without any stimulus. The model was evaluated from mental and physical fatigue on the 8th day and 15th day. The mental fatigue was evaluated by a water maze test and the rat's 5-hydroxytryptamine (5-HT) level in hippocampus, while the physical fatigue was evaluated using lactic acid level in serum and duration of weight-loaded forced swimming.

Results: Among the 7-day and 14-day modeling groups, compared with the control group, the success rate of water maze landing was significantly decreased, the time for water maze landing was significantly prolonged and 5-HT level in hippocampus significantly decreased in the fatigue group. With respect to physical fatigue, among the 7-day and 14-day modeling groups, the lactic acid level in serum in the fatigue group was significantly increased, and the duration of exhaustive swimming of rats was significantly shortened.

Limitations: A small sample size was the main limitation of this study.

Conclusions: We have successfully constructed a rat model of postpartum fatigue by forcing postpartum rats to stand in water, which was similar to a level of stress that contributes to the development of postpartum fatigue. Our model opens the door for future studies evaluating the effectiveness of pharmacological and behavioral therapies.
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http://dx.doi.org/10.1159/000517997DOI Listing
September 2021

A Review: Microbial Diversity and Function of Fermented Meat Products in China.

Front Microbiol 2021 7;12:645435. Epub 2021 Jun 7.

Key Laboratory for Meat Processing of Sichuan Province, Chengdu University, Chengdu, China.

Fermented meat products have a long history in China. These products exhibit a characteristic unique flavor, compact meat quality, clear color, long shelf life and wide variety and are easy to transport. During the processing and storage of fermented meat products, microorganisms are present and exhibit diverse characteristics. Microorganisms can accelerate the degradation of proteins and fats to produce flavor compounds, inhibit the growth and reproduction of heterozygous bacteria, and reduce the content of chemical pollutants. This paper reviews the microbial diversity of Chinese ham, sausage, preserved meat, pressed salted duck, preserved fish and air-dried meat and provides analyses of the microbial compositions of various products. Due to the differences in raw materials, technology, auxiliary materials, and fermentation technology, the microbial species found in various fermented meat products in China are different. However, most fermented meat products in China are subjected to pickling and fermentation, so their microbial compositions also have similarities. Microorganisms in fermented meat products mainly include staphylococci, lactobacilli, micrococci, yeasts, and molds. The study of microbial diversity is of great significance for the formation of quality flavor and the safety control of fermented meat products, and it provides some theoretical reference for the study of fermented meat products in China.
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http://dx.doi.org/10.3389/fmicb.2021.645435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215344PMC
June 2021

Follow-up in Patients With Non-invasive Prenatal Screening Failures: A Reflection on the Choice of Further Prenatal Diagnosis.

Front Genet 2021 19;12:666648. Epub 2021 May 19.

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

Background: Our aim was to provide a theoretical basis for clinicians to conduct genetic counseling and choose further prenatal diagnosis methods for pregnant women who failed non-invasive prenatal screening (NIPS).

Methods: A retrospective analysis was performed on pregnant women who had failed NIPS tests.

Results: Among the 123,291 samples, 394 pregnant women did not obtain valid results due to test failures. A total of 378 pregnant women were available for follow-up, while 16 patients were lost to follow-up. Of these 378, 135 pregnant women chose further prenatal diagnosis through amniocentesis, and one case of dysplasia was recalled for postpartum chromosome testing. The incidence rate of congenital chromosomal abnormalities in those who failed the NIPS was 3.97% (15/378), which was higher than that of the chromosomal abnormalities in the common population (1.8%). Among the pregnant women who received prenatal diagnosis, the positive rates of chromosomal abnormalities in the chromosomal microarray analysis/copy number variation sequencing (CMA/CNV-seq) group and in the karyotyping group were 15.28 and 4.76%, respectively.

Conclusion: Prenatal diagnosis should be strongly recommended in posttest genetic counseling for pregnant women with NIPS failures. Further, high-resolution detection methods should be recommended for additional prenatal diagnoses.
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http://dx.doi.org/10.3389/fgene.2021.666648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172122PMC
May 2021

Structure validation of oxidized poly (2-hydroxyethyl acrylate) with multiple aldehyde groups and its application for collagen modification.

R Soc Open Sci 2021 Feb 17;8(2):201892. Epub 2021 Feb 17.

College of Food and Biological Engineering, Sichuan Key Laboratory of Meat Processing, Chengdu University, Chengdu, Sichuan 610106, People's Republic of China.

The structural characteristic of oxidized poly (2-hydroxyethyl acrylate) (OP) was confirmed by high-performance liquid chromatography, gel permeation chromatography and hydroxylamine hydrochloride titration. The results demonstrated that OP prepared through 2,2,6,6-tetramethylpiperidine-1-oxyl-mediated oxidation of poly (2-hydroxyethyl acrylate) was featured by multiple aldehyde groups on its side chain, with no free formaldehyde produced during the oxidation process. The computational simulation for the electrophilic reactivity of OP molecule showed that the reactivity of the aldehyde groups in OP with the amino groups of collagen was comparable to that of glutaraldehyde. In this study, OP was chosen as a collagen modifier to investigate the modification effects on the secondary structure, aggregation behaviour and thermal stability of collagen. The covalent cross-linking occurred between the aldehyde groups of OP and the amino groups of collagen under alkaline condition. The covalent binding between OP and collagen was strengthened with the increasing reaction pH and OP dosage, and the triple helix of collagen was altered to some degree. Furthermore, OP promoted the intense aggregation of collagen and enhanced the thermal stability of collagen. This work provides guidance for preparing novel collagen modifier with multiple aldehyde groups.
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http://dx.doi.org/10.1098/rsos.201892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074665PMC
February 2021

Characterization of umami compounds in bone meal hydrolysate.

J Food Sci 2021 Jun 4;86(6):2264-2275. Epub 2021 May 4.

State Key Laboratory of Bioreactor Engineering, R&D Center of Separation and Extraction Technology in Fermentation Industry, East China University of Science and Technology, Shanghai, China.

The objective of this research was to identify and characterize the chemical compounds that exhibited monosodium glutamate (MSG)-like taste in the hydrolyzed bone meal produced by using flavourzyme. The free amino acids and peptides in the bone meal hydrolysate were analyzed. The results showed that the glutamic acid and the aspartic acid in the bone meal increased by 13.1 times and 14.2 times, respectively, after the flavourzyme hydrolysis. The peptides' isolation identified six MSG-like peptides in the hydrolysate, including APGPVGPAG, DAINWPTPGEIAH, FLGDEETVR, GVDEATIIEILTK, PAGPVGPVG, and VAPEEHPTL, which should contribute to the taste. The human sensory evaluation results indicated that the six peptides showed MSG-like taste, and the electronic tongue analysis indicated that the six peptides showed sourness, saltiness, bitterness, and astringency. The findings of this study demonstrated that the MSG-like taste of the bone meal hydrolysate should be attributed to the generation of MSG-like amino acids and peptides from the flavourzyme hydrolysis. PRACTICAL APPLICATION: The manuscript describes the umami compounds in the bone meal hydrolysate. The findings from this study should further confirm the feasibility of using bone meal to prepare meat-flavor essence and provide a better understanding of preparing bio-source flavoring peptides, which is very important to the artificial meat development and gene breeding.
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http://dx.doi.org/10.1111/1750-3841.15751DOI Listing
June 2021

Effects of climate change on ecosystem services and their components in southern hills and northern grasslands in China.

Environ Sci Pollut Res Int 2021 Sep 14;28(33):44916-44935. Epub 2021 Apr 14.

Key Laboratory of Ecology and Environment in Minority Areas (Minzu University of China), National Ethnic Affairs Commission, Beijing, 100081, China.

We investigated the potential impacts of climate change on ecosystem services and their components in two distinct ecosystems: the northern grasslands and southern hills in China. The effects of minimum, average, and maximum temperature, and precipitation at monthly, seasonal, and yearly scales on ecosystem services and their components were studied through stepwise multiple regression analysis. The results showed that in the northern grasslands, an increase in the total ecosystem services value (ESV) was mainly attributed to soil conservation, biodiversity, hydrological regulation, and aesthetic landscape. In the southern hills, an increase in total ESV in each region was mainly attributed to climate regulation, environmental purification, biodiversity, and aesthetic landscape. There were strong correlations between ESVs and fluctuations in temperature and precipitation. In the northern grasslands, temperature was the main driving factor of the values from 11 categories of ecosystem services in Anxi, Tumuji, and Xilingol. However, in West Ordos, precipitation negatively affected the change in ESVs. In the southern hills, ESVs were governed by both precipitation and temperature in Huaying. Precipitation variables were an important factor affecting the ESVs in Cili. There was a stronger correlation between temperature and the majority of ESVs in Danjiangkou, Chongyi, and Lechang than precipitation. This paper provides a basis for a better understanding of the impact of climate change on different ecosystem services, and helps to enhance ESV under climate warming.
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http://dx.doi.org/10.1007/s11356-021-13699-8DOI Listing
September 2021

Association of human papillomavirus genotype distribution and cervical cytology: a cross-sectional study.

Epidemiol Infect 2021 04 12;149:e95. Epub 2021 Apr 12.

Institute of Health Policy & Hospital Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

The present study attempted to analyse human papillomavirus (HPV) genotype distribution and its association with cervical cytology results in women in western China. The present retrospective analysis was performed in 1089 female outpatients with a positive HPV test result who had undergone a cervical cytology test at the gynaecological clinic, West China Second Hospital, Sichuan University, China, between January 2014 and December 2016. Of the 1089 patients with HPV infection, multiple HPV genotypes were detected in 220 patients (20.20%). Among the 1368 HPV genotypes detected, 1145 (83.70%) were high-risk subtypes. The most common genotypes were HPV-52 (18.64%), HPV-16 (16.59%), HPV-58 (13.23%), HPV-18 (6.80%), HPV-56 (5.56%) and HPV-59 (5.56%). Cervical cytology revealed abnormal cells in 430 (39.49%) patients. The most common diagnoses were atypical squamous cells of undetermined significance (ASC-US; 236 cases, 54.88%), low-grade squamous intraepithelial lesions (LSIL; 151 cases, 35.12%), high-grade squamous intraepithelial lesions (HSIL; 63 cases, 14.65%) and atypical glandular cells (AGC; 21 cases, 4.88%). HPV-66 was significantly associated (P = 0.037) with ASC; HPV-52 and HPV-56 were significantly associated with LSIL (P = 0.009 and 0.026, respectively); HPV-16 (P < 0.001), HPV-33 (P = 0.014) and HPV-58 (P = 0.003) were significantly associated with HSIL; and HPV-16 (P = 0.005) was significantly associated with AGC. HPV-16, HPV-52 and HPV-58 are associated with different diagnoses in patients with positive cervical cytological findings.
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http://dx.doi.org/10.1017/S0950268821000741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080181PMC
April 2021

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

Mutation pattern and genotype-phenotype correlations of SETD2 in neurodevelopmental disorders.

Eur J Med Genet 2021 May 23;64(5):104200. Epub 2021 Mar 23.

Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, China. Electronic address:

SETD2 encodes an important protein for epigenetic modification of histones which plays an essential role in early development. Variants in SETD2 have been reported in neurodevelopmental disorders including autism spectrum disorder (ASD). However, most de novo SETD2 variants were reported in different large-cohort sequencing studies, mutation pattern and comprehensive genotype-phenotype correlations for SETD2 are still lacking. We have applied target sequencing to identify rare, clinical-relevant SETD2 variants and detected two novel de novo SETD2 variants, including a de novo splicing variant (NM_014159: c.4715+1G>A) and a de novo missense variant (c.3185C>T: p.P1062L) in two individuals with a diagnosis of ASD. To analyze the correlations between SETD2 mutations and corresponding phenotypes, we systematically review the reported individuals with de novo SETD2 variants, classify the pathogenicity, and analyze the detailed phenotypes. We subsequently manually curate 17 SETD2 de novo variants in 17 individuals from published literature. Individuals with de novo SETD2 variants present common phenotypes including speech and motor delay, intellectual disability, macrocephaly, ASD, overgrowth and recurrent otitis media. Our study reveals new SETD2 mutations and provided a relatively homozygous phenotype spectrum of SETD2-related neurodevelopmental disorders which will be beneficial for disease classification and diagnosis in clinical practice.
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http://dx.doi.org/10.1016/j.ejmg.2021.104200DOI Listing
May 2021

Flavor Composition and Microbial Community Structure of Mianning Ham.

Front Microbiol 2020 26;11:623775. Epub 2021 Jan 26.

Key Lab of Meat Processing of Sichuan Province, Chengdu University, Chengdu, China.

Mianning ham, a traditional Chinese dry-cured ham, is protected by national geographical indications. To understand the surface and internal flavor composition and microbial community structure of Mianning ham, solid phase microextraction-gas chromatography (SPME-GC-MS) technology and Illumina high-throughput sequencing were utilized. The results showed that a total of 60 flavor substances were identified in the hams. Forty-nine kinds of flavorings were identified on the surface, including 14 aldehydes, 6 ketones, 10 alcohols, 5 esters, 7 hydrocarbons, 5 acids, and 2 other compounds. Thirty-six kinds of internal flavorings were identified, including 13 aldehydes, 4 ketones, 6 alcohols, 3 esters, 5 hydrocarbons, 4 acids and 1 other type. Decanal (34.91 μg/g) was the most prevalent compound on the surface, followed by n-hexanol (24.99 μg/g), n-hexanal (20.20 μg/g), and n-octyl (16.14 μg/g). n-Hexanal (20.74 μg/g) was the most common compound internally, followed by non-aldehyde (5.70 μg/g), 1-octene-3-alcohol (3.54 μg/g), and inverse-2-octenal (2.77 μg/g). , and were isolated from the surfaces of the hams by the traditional culture method. By Illumina high-throughput sequencing, three fungal phyla were identified. Ascomycota was the dominant phylum followed by Basidiomycota. At the genus level, 11 fungi were identified, of which was the dominant fungus, followed by and . These findings provide fundamental knowledge regarding the microorganisms and flavor compounds in Mianning ham, which will help industrial processors develop effective strategies for standardizing quality parameters.
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http://dx.doi.org/10.3389/fmicb.2020.623775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870506PMC
January 2021

Silencing TLR4/MyD88/NF-κB Signaling Pathway Alleviated Inflammation of Corneal Epithelial Cells Infected by ISE.

Inflammation 2021 Apr 10;44(2):633-644. Epub 2020 Nov 10.

Laboratory Animal Center, Nantong University, Nantong, 226001, China.

The regulatory role of toll-like receptor 4 (TLR4) in the inactivate staphylococcus epidermidis (ISE)-induced cornea inflammation is not well investigated. Here, TLR4 silence could decrease inflammatory cytokines in corneal epithelial cells treated with ISE. The mouse corneal epithelial cells were exposed to ISE for 24 h, either alone or with the NF-κB inhibitor, TLR4 lentivirus to bilaterally (knock-down or and overexpression). The expression of TLR4 in mouse corneal epithelial cells was investigated using western blot and qRT-PCR assay. The inflammatory cytokine levels were evaluated by qRT-PCR and ELISA, respectively. The relative impact factors of TLR4-mediated NF-κB signaling detected using western blot assay. Results show the expression levels of TLR4 and some inflammatory cytokines were significantly increased in corneal epithelial cells treated with ISE. TLR4 Silence markedly decreased ISE-induced production of IL12, TNF-α, CCL5, and CCL9 in corneal epithelial cells. Furthermore, the nuclear translocation of NF-κB p65 and myeloid differentiation protein 88 (MyD88) in the cells treated with ISE were further reduced by silencing TLR4. Inhibition of TLR4-mediated NF-κB signaling by using BAY11-7082 also alleviated ISE-induced inflammation. In the rescue experiment, transfected the stable TLR4 silenced corneal epithelial cells with TLR4 overexpression lentivirus, we found that TLR4 overexpression can restore the down-regulation of TLR4 and inflammatory cytokines (IL12, TNF-α, CCL9) caused by TLR4 knocked down. Therefore, ISE-induced cornea inflammation was due to the activation of the TLR4/MyD88/NF-κB signaling pathway, and dramatically stimulated IL12, TNF-α, CCL9 secretion. TLR4 silence presented mitigates damage in corneal epithelial cells treated with ISE.
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http://dx.doi.org/10.1007/s10753-020-01363-1DOI Listing
April 2021

Our Experiences with Plastic and Reconstructive Surgery Procedures during Coronavirus Disease 2019 Pandemic.

Plast Reconstr Surg Glob Open 2020 May 13;8(5):e2868. Epub 2020 May 13.

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The novel Coronavirus Disease 2019 (COVID-19) has rapidly become a health threat worldwide and has been declared global pandemic by the World Health Organization. Possible transmission routes, including respiratory droplets, close contact, and aerosol propagation, have put plastic and reconstructive healthcare professionals at high risk, especially during surgical procedures. The aim of this study was to summarize and share our experience of infection control measures and corresponding outcomes during the COVID-19 pandemic.

Methods: Infection control measures, including workflow optimization, useful epidemiologic survey methods, and personal full protective clothing, were discussed. Characteristics and outcomes of emergency cases and elective cases under local and general anesthesia during the COVID-19 pandemic were summarized.

Results: A hierarchy of interventions were applied mainly from 4 aspects. First, administration control and online consultation significantly decreased patient attendance. Second, a triage workflow was established to identify high-/low-risk patients, with clinical manifestations (fever, fatigue, cough, nasal discharge, etc), epidemiologic survey, blood test, chest computed tomographic scan, and coronavirus test if necessary. Third, strict environmental control was adopted using increasing ventilation, isolated room for inpatients, etc. Fourth, proper rotation of healthcare staff was ensured to reduce workload and minimize possible contact. A total of 904 emergency interventions, 2561 local anesthesia, and 570 general anesthesia were performed during this period, and none of the cases/healthcare professionals were found to be infected.

Conclusions: Our experience could help global plastic and reconstructive healthcare professionals to get better preparation and continue to give qualified medical services during the COVID-19 pandemic. Proper adjustments should be taken according to their own clinical settings.
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http://dx.doi.org/10.1097/GOX.0000000000002868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572092PMC
May 2020

Blocking ACAT-1 Activity for Tumor Therapy with Fluorescent Hyperstar Polymer-Encapsulated Avasimible.

Macromol Biosci 2020 07 13;20(7):e1900438. Epub 2020 May 13.

Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi'an, 710072, P. R. China.

Targeting the distinct cholesterol metabolism of tumor cells is proposed as a novel way to treat tumors. Blocking acyl-CoA cholesterol acyltransferase-1 (ACAT-1) by the inhibitor avasimible (Ava), which elevates intracellular free cholesterol levels, is shown to effectively induce apoptosis. However, Ava faces disadvantages of poor water solubility, a short half-life, and no capability for fluorescence detection, which have greatly limited its application. Herein, a fluorescent hyperstar polymer (FHSP) is developed to encapsulate Ava to improve its ability to inhibit HeLa cells and K562 cells. The results of this study show that the obtained Ava-FHSP micelles possess a high drug loading capacity of 22.7% and bright green fluorescence. Ava and Ava-FHSP are cytotoxic to both HeLa and K562 cells and cause reductions in cell size, nuclear lysis, and chromatin condensation and hindered proliferation of both cell types by causing S phase cell cycle arrest. Further mechanistic analysis indicates that Ava-FHSP reduces the protein and messenger RNA expression of ACAT-1 and significantly increases intracellular free cholesterol levels, which can increase endoplasmic reticulum stress and finally cause cell apoptosis. All these results suggest that this fluorescent hyperstar polymer represents a potential therapeutic tumor strategy by changing the cholesterol metabolism of tumor cells.
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http://dx.doi.org/10.1002/mabi.201900438DOI Listing
July 2020

Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.

Clin Genet 2020 02 14;97(2):338-346. Epub 2019 Nov 14.

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.

The genotype-first approach has been successfully applied and has elucidated several subtypes of autism spectrum disorder (ASD). However, it requires very large cohorts because of the extensive genetic heterogeneity. We investigate the alternate possibility of whether phenotype-specific genes can be identified from a small group of patients with specific phenotype(s). To identify novel genes associated with ASD and abnormal head circumference using a phenotype-to-genotype approach, we performed whole-exome sequencing on 67 families with ASD and abnormal head circumference. Clinically relevant pathogenic or likely pathogenic variants account for 23.9% of patients with microcephaly or macrocephaly, and 81.25% of those variants or genes are head-size associated. Significantly, recurrent pathogenic mutations were identified in two macrocephaly genes (PTEN, CHD8) in this small cohort. De novo mutations in several candidate genes (UBN2, BIRC6, SYNE1, and KCNMA1) were detected, as well as one new candidate gene (TNPO3) implicated in ASD and related neurodevelopmental disorders. We identify genotype-phenotype correlations for head-size-associated ASD genes and novel candidate genes for further investigation. Our results also suggest a phenotype-to-genotype strategy would accelerate the elucidation of genotype-phenotype relationships for ASD by using phenotype-restricted cohorts.
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http://dx.doi.org/10.1111/cge.13665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307605PMC
February 2020

Genome-wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders.

Autism Res 2020 03 24;13(3):382-396. Epub 2019 Oct 24.

Mental Health Institute, The Second Xiangya Hospital, Central South University, Changsha, China.

Autism is a common neurodevelopmental disorder with a moderate to a high degree of heritability, but only a few common genetic variants that explain the heritability have been associated. We performed a genome-wide transmission disequilibrium test analysis of a newly genotyped autism case-parent triad samples (127 trios) in Han Chinese, identified top association signals at multiple single nucleotide polymorphisms (SNPs), including rs9839376 (OR = 2.59, P = 1.27 × 10 ) at KCNMB2, rs6044680 (OR = 0.319, P = 4.82 × 10 ) and rs7274133 (OR = 0.313, P = 3.22 × 10 ) at PCSK2, and rs310619 (OR = 2.40, P = 7.44 × 10 ) at EEF1A2. Furthermore, a genome-wide combined P-value of individual SNPs in two independent case-parent triad samples (total 402 triads, n = 1,206) identified SNPs at EGFLAM, ZDHHC2, AGBL1, and SNX29 as additional association signals for autism. While none of these signals achieved a genome-wide significance in the two samples of our study, they have been reported in a previous genome-wide association study of neuropsychiatric disorders, and the majority of these SNP have a significant cis-regulatory association with mRNA in human tissues (false discovery rate (FDR) < 0.05). Our study warrants further study or replication with additional sample for association with autism and other neuropsychiatric disorders. Autism Res 2020, 13: 382-396. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism is a common neurodevelopmental disorder, heritable, but only a few common genetic variants that explain the heritability have been associated. We conducted a genome-wide association study with two cohorts of autism case-parent triad samples in Han Chinese and identified multiple single nucleotide polymorphisms that were reported as strong association signals in a previous genome-wide association study of other neuropsychiatric disorders or related traits. Our study provides evidence for shared genetic variants among autism and other neuropsychiatric disorders.
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http://dx.doi.org/10.1002/aur.2229DOI Listing
March 2020

Disruptive variants of associate with autism and interfere with neuronal development and synaptic transmission.

Sci Adv 2019 09 25;5(9):eaax2166. Epub 2019 Sep 25.

Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.
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http://dx.doi.org/10.1126/sciadv.aax2166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760934PMC
September 2019

POGZ de novo missense variants in neuropsychiatric disorders.

Mol Genet Genomic Med 2019 09 25;7(9):e900. Epub 2019 Jul 25.

Center of Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

Background: De novo likely gene-disrupting variants of POGZ cause autism spectrum disorder (ASD) and intellectual disability. However, de novo missense variants of this gene were not well explored in neuropsychiatric disorders.

Methods: The single-molecule molecular inversion probes-based targeted sequencing method was performed on the proband. Variant was validated using Sanger sequencing in both proband and parents. Immunoblot analysis was performed to examine the expression of POGZ in patient-derived peripheral blood lymphocytes. Published POGZ de novo missense variants in neuropsychiatric disorders were reviewed.

Results: We detected a novel de novo missense variant in POGZ (c.1534C>A, p.H512N, NM_015100.4) in an individual with ASD. Immunoblot analysis revealed a dramatic reduction in POGZ protein in patient-derived peripheral blood lymphocytes suggesting a loss-of-function mechanism of this de novo missense variant. In addition, we collected and annotated additional eight POGZ de novo missense variants identified in neuropsychiatric disorders from literatures.

Conclusion: Our findings will be beneficial to the functional analysis of POGZ in ASD pathogenesis, and for genetic counseling and clinical diagnosis of patients with POGZ de novo missense variants.
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http://dx.doi.org/10.1002/mgg3.900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732319PMC
September 2019

Pathogenic missense mutation pattern of forkhead box genes in neurodevelopmental disorders.

Mol Genet Genomic Med 2019 07 14;7(7):e00789. Epub 2019 Jun 14.

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.

Background: Forkhead box (FOX) proteins are a family of transcription factors. Mutations of three FOX genes, including FOXP1, FOXP2, and FOXG1, have been reported in neurodevelopmental disorders (NDDs). However, due to the lack of site-specific statistical significance, the pathogenicity of missense mutations of these genes is difficult to determine.

Methods: DNA and RNA were extracted from peripheral blood lymphocytes. The mutation was detected by single-molecule molecular inversion probe-based targeted sequencing, and the variant was validated by Sanger sequencing. Real-time quantitative PCR and western blot were performed to assay the expression of the mRNA and protein. To assess the pattern of disorder-related missense mutations of NDD-related FOX genes, we manually curated de novo and inherited missense or inframeshift variants within FOXP1, FOXP2, and FOXG1 that co-segregated with phenotypes in NDDs. All variants were annotated by ANNOVAR.

Results: We detected a novel de novo missense mutation (NM_001244815: c.G1444A, p.E482K) of FOXP1 in a patient with intellectual disability and severe speech delay. Real-time PCR and western blot revealed a dramatic reduction of mRNA and protein expression in patient-derived lymphocytes, indicating a loss-of-function mechanism. We observed that the majority of the de novo or transmitted missense variants were located in the FOX domains, and 95% were classified as pathogenic mutations. However, 10 variants were located outside of the FOX domain and were classified as likely pathogenic or variants of uncertain significance.

Conclusion: Our study shows the pathogenicity of missense and inframeshift variants of NDD-related FOX genes, which is important for clinical diagnosis and genetic counseling. Functional analysis is needed to determine the pathogenicity of the variants with uncertain clinical significance.
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http://dx.doi.org/10.1002/mgg3.789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625093PMC
July 2019

Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development.

J Genet Genomics 2019 05 18;46(5):247-257. Epub 2019 May 18.

Center of Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, China; School of Life Sciences and Technology, Xinjiang University, Ürümqi, 830046, China; CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, 200030, China. Electronic address:

Excess de novo likely gene-disruptive and missense variants within dozens of genes have been identified in autism spectrum disorder (ASD) and other neurodevelopmental disorders. However, many rare inherited missense variants of these high-risk genes have not been thoroughly evaluated. In this study, we analyzed the rare missense variant burden of POGZ in a large cohort of ASD patients from the Autism Clinical and Genetic Resources in China (ACGC) and further dissected the functional effect of disease-associated missense variants on neuronal development. Our results showed a significant burden of rare missense variants in ASD patients compared to the control population (P = 4.6 × 10, OR = 3.96), and missense variants in ASD patients showed more severe predicted functional outcomes than those in controls. Furthermore, by leveraging published large-scale sequencing data of neurodevelopmental disorders (NDDs) and sporadic case reports, we identified 8 de novo missense variants of POGZ in NDD patients. Functional analysis revealed that two inherited, but not de novo, missense variants influenced the cellular localization of POGZ and failed to rescue the defects in neurite and dendritic spine development caused by Pogz knockdown in cultured mouse primary cortical neurons. Significantly, L1CAM, an autism candidate risk gene, is differentially expressed in POGZ deficient cell lines. Reduced expression of L1cam was able to partially rescue the neurite length defects caused by Pogz knockdown. Our study showed the important roles of rare inherited missense variants of POGZ in ASD risk and neuronal development and identified the potential downstream targets of POGZ, which are important for further molecular mechanism studies.
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http://dx.doi.org/10.1016/j.jgg.2019.04.002DOI Listing
May 2019

pH-responsive dithiomaleimide-amphiphilic block copolymer for drug delivery and cellular imaging.

J Colloid Interface Sci 2019 Sep 23;552:439-447. Epub 2019 May 23.

Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi'an 710072, PR China. Electronic address:

A drug delivery system that is integrated with fluorescent imaging is an emerging platform for tumor diagnostic and therapy. A pH-responsive fluorescent polymer that can respond to the surrounding medium is a desired component with which to construct an advanced drug delivery system with bioimaging characteristics and controllable drug releasing. In this work, we synthesized novel amphiphilic block copolymers of poly(ethylene glycol)-b-poly(2-(diisopropylamino) ethyl methacrylate-co-dithiomaleimide) (PEG-b-poly(DPA-co-DTM)) and poly(ethylene glycol)-b-poly(2-(dibutylamino) ethyl methacrylate-co-dithiomaleimide) (PEG-b-poly(DBA-co-DTM)) with pH-responsiveness and fluorescence. The block copolymers exhibited relatively stable fluorescence properties in different solvent and excitation-independent fluorescence behaviours. By copolymerizing the responsive segments in the molecule chain, the doxorubicin (DOX)-loaded micelles could be triggered to disassemble, thus releasing DOX at the corresponding pH values and yielding a pH-responsive drug release. Targeted deliveries of the drug within the cell were demonstrated by using the carrier responding to different pH values. The best antitumor effect was obtained by PEG-b-poly(DPA-co-DTM), which immediately released DOX as soon as it entered the tumor cells, as a result of responding to the regional pH level (pH = 6.3). The pH-responsive copolymers showed excellent biocompatibilities, as nearly 85% of cells with these fluorescent micelles survive when the testing concentration goes up to 200 μg mL. In all, these pH-responsive and dithiomaleimide-based fluorescent block copolymers hold great potential in future cancer diagnostic and therapeutic techniques.
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http://dx.doi.org/10.1016/j.jcis.2019.05.074DOI Listing
September 2019

Clinical application of noninvasive prenatal screening for sex chromosome aneuploidies in 50,301 pregnancies: initial experience in a Chinese hospital.

Sci Rep 2019 05 23;9(1):7767. Epub 2019 May 23.

Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University,, Chengdu, 610041, China.

To evaluate the clinical performance of noninvasive prenatal screening (NIPS) for fetal sex chromosome aneuploidies (SCAs), pregnant women were recruited in this retrospective observational study. The NIPS test was undertaken using high-throughput gene sequencing. In total,50,301 pregnant women were analysed for demographic characteristics and medical history. Of them, 308 women (0.61%) had high risk for fetal SCAs, including 138 for 45,X, 111 for 47,XXY, 42 for 47,XXX, and 17 for 47,XYY. After the pre-test counselling, 182 participants chose to undergo invasive prenatal diagnosis, confirming 59 positive cases. The combined positive predictive value of NIPS was 32.42% (59/182), 18.39% (16/87), 44.4% (12/27), 39.29% (22/56), and 75% (9/12) for detecting SCAs, 45,X, 47,XXX, 47,XXY, and 47,XYY, respectively. NIPS can be a useful method to detect the fetal SCAs using high-throughput gene sequencing, though accuracy can still be improved, especially for 45,X. Although the value of NIPS compare favorably with those seen in traditional screening approaches for SCAs, it is important to highlight the limitations of NIPS while educating clinicians and patients.
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http://dx.doi.org/10.1038/s41598-019-44018-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533246PMC
May 2019

Synthesis of Novel pH-Tunable Thermoresponsive Hydroxyl-Terminated Hyperbranched Polyether.

Polymers (Basel) 2019 May 16;11(5). Epub 2019 May 16.

The Key Laboratory of Space Applied Physics and Chemistry, Ministry of Education and Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi'an 710072, China.

In this study, a new pH-tunable thermoresponsive hydroxyl-terminated hyperbranched polyether (HTHP 2) was successfully prepared via a one-pot cationic polymerization technique and postmodification. In the first step, hydroxyl-terminated hyperbranched polyether containing double bonds (HTHP 1) were synthesized. Then, through thiol-ene "click" reaction, pH-responsive carboxyl groups were introduced to the target polymer of HTHP 2. The products were characterized via Fourier-transform infrared spectra (FTIR), nuclear magnetic resonance (NMR), and size-exclusion chromatography-multiangle laser light scattering (SEC-MALLS). Moreover, dynamic light scattering (DLS) and UV-Vis spectroscopy was employed to study the pH- and thermoresponsiveness in detail. Results showed that HTHP 2 possessed typical pH-controllable thermoresponsive behavior. By regulating the solution pH value range 3.0-5.4, LCST of HTHP 2 could be changed from 12.8 to 68.0 °C. Meanwhile, the cell viabilities of A549 cells were more than 80% for in vitro cytotoxicity tests of HTHP 2, suggested that HTHP 2 polymers are of good biocompatibility for up to 24 h.
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http://dx.doi.org/10.3390/polym11050895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572042PMC
May 2019

Thymoquinone Attenuates Acetaminophen Overdose-Induced Acute Liver Injury and Inflammation Via Regulation of JNK and AMPK Signaling Pathway.

Am J Chin Med 2019 11;47(3):577-594. Epub 2019 Apr 11.

* Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Clinical Research Center, Yanbian University Hospital, Yanji 133002, Jilin Province, China.

Thymoquinone (TQ) is a main aromatic component of L. seeds or (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24 h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1 release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.
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http://dx.doi.org/10.1142/S0192415X19500307DOI Listing
October 2019

Synthesis and Properties of Side-Chain Functionalized Polytetrahydrofuran Derivatives via the Blue-Light Photocatalytic Thiol-Ene Reaction.

Polymers (Basel) 2019 Apr 1;11(4). Epub 2019 Apr 1.

The Key Laboratory of Space Applied Physics and Chemistry, Ministry of Education and Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi'an 710072, China.

A series of side-chain functionalized polytetrahydrofuran (PTHF) derivatives were synthesized via the blue-light photocatalytic thiol-ene "click" reaction. Firstly, unsaturated polytetrahydrofuran (UPTHF) as a new unsaturated polyether was synthesized via condensation polymerization of cis-2-butene-1,4-diol and trans-1,4-dibromo-2-butene using potassium hydroxide (KOH) as a catalyst. Then, double bonds in the backbone of UPTHF were modified into different pendant functionality side groups by blue-light photocatalytic thiol-ene "click" reaction using Ru(bpy)₃Cl₂ as a photoredox catalyst, obtaining different side-chain functionalized PTHF derivatives. The structure and the morphology of the side-chain functionalized PTHF derivatives was characterized via Fourier-transform infrared spectra (FTIR), nuclear magnetic resonance (NMR), size exclusion chromatography/multi-angle laser light scattering (SEC/MALLS), and differential scanning calorimeter (DSC). The results showed that the blue-light photocatalytic thiol-ene reaction exhibited high efficiency, and all the unsaturated bonds were modified. Different branch units bestowed different performance of PTHF derivatives; we systematically investigated the thermal properties, pH-triggered and temperature-triggered, self-assembly behaviors of different PTHF derivatives.
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http://dx.doi.org/10.3390/polym11040583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523133PMC
April 2019

Early Feeding Behaviors and Breastfeeding Outcomes After Cesarean Section.

Breastfeed Med 2019 06 13;14(5):325-333. Epub 2019 Mar 13.

Department of Clinical Nursing, School of Nursing, Nantong University, Nantong, China.

To explore the relationship of early breastfeeding behaviors after Cesarean section (CS) to long-term breastfeeding outcome. A total of 648 healthy breastfeeding primiparas (333 delivered by CS, and 315 by vaginal birth) were recruited from three teaching hospitals using probability proportional to size sampling method. Data of the first 3 days breastfeeding behaviors, including breastfeeding initiation, frequency and duration, formula supplement, and infant sucking performance, were gathered. Ordinal cumulative odds logistic regression model were conducted to explore the effect of CS on breastfeeding outcome at fifth day, and first, fourth, and sixth month before and after adjusting for the variants of early breastfeeding behaviors. The unadjusted odds ratios (ORs) for lower breastfeeding rates associated with CS were 2.11 (95% confidence interval [CI]: 1.58-2.81), 2.67 (95% CI: 1.96-3.63), 1.60 (95% CI: 1.19-2.15), and 1.36 (95% CI: 1.01-1.83) at the fifth day, and first, fourth, and sixth month. After adjusting for the early breastfeeding behaviors, the negative effect of CS on long-term breastfeeding was attenuated, and no longer significant at fifth day (OR: 1.01, 95% CI: 0.70-1.47) and fourth month (OR: 1.13, 95% CI: 0.79-1.62) and sixth month (OR: 0.81, 95% CI: 0.56-1.17). CS had a detrimental effect on early breastfeeding behaviors and long-term breastfeeding outcomes. CS per se is not a negative factor, but rather those infants who have feeding difficulties in the immediate postpartum period have long-term problems.
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http://dx.doi.org/10.1089/bfm.2018.0150DOI Listing
June 2019

Upregulated expression of serum exosomal miR-375 and miR-1307 enhance the diagnostic power of CA125 for ovarian cancer.

J Ovarian Res 2019 Jan 22;12(1). Epub 2019 Jan 22.

The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, Jiangsu, China.

Background: Ovarian cancer (OC) is associated with high mortality in gynecological oncology; this is mainly due to the low diagnosis rate. Exosomal miRNA has demonstrated potential as a tumor biomarker. We aimed to explore the diagnostic potential of serum exosomal miR-1307 and miR-375 for OC.

Methods: The first six candidate miRNAs were selected from the previous literature. The relative quantification of qRT-PCR was used to screen for the stability of exosomal miRNAs, followed by validation of the cohort. ROC analysis was employed to analyze the specificity and sensitivity of exosomal miRNA.

Results: MiR-1307 and miR-375 were confirmed stably existing in serum exosomes of OC. Moreover, miR-1307 and miR-375 were both significantly up-regulated in serum exosomes of OC compared to ovarian benign and healthy groups. The overexpressed miRNAs showed independent diagnostic power and enhanced the diagnostic accuracy of traditional biomarkers when combined with CA-125 and HE4. MiR-1307 was associated with tumor staging, and miR-375 was associated with lymph node metastasis of OC.

Conclusion: Our results suggest that serum exosomal miR-1307 and miR-375 could serve as potential tumor biomarkers to improve diagnostic efficiency for OC.
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http://dx.doi.org/10.1186/s13048-018-0477-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341583PMC
January 2019

Sleep Deprivation Induces Dry Eye Through Inhibition of PPARα Expression in Corneal Epithelium.

Invest Ophthalmol Vis Sci 2018 11;59(13):5494-5508

Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Medical College, Xiamen University, Xiamen, Fujian, China.

Purpose: To determine if sleep deprivation induces dry eye through altering peroxisome proliferator-activated receptor alpha (PPARα) expression in mice.

Methods: The "stick over water" sleep deprivation-induced dry eye (SDE) model evaluated PPARα involvement in inducing this condition. Scanning electron microscopy (SEM) examined microvilli morphology in superficial corneal epithelial cells (SCECs) in SDE and PPARα-/- mice. Quantitative RT-PCR (qRT-PCR) and Western blot (WB) or immunostaining evaluated PPARα, carnitine palmitoyl transferase 1α (CPT1α), and transient receptor potential vanilloid 6 (TRPV6) expression levels and Ezrin phosphorylation status. Hematoxylin-eosin and Oil Red O staining characterized meibomian gland morphology and corneal lipid accumulation, respectively. Phenol red cotton threads measured tear production. In cultured corneal epithelial sheets, qRT-PCR, WB, and SEM determined the individual effects of fenofibrate and MK886 (PPARα agonist and antagonist, respectively) on PPARα, TRPV6 expression, and SCEC microvilli morphology.

Results: Corneal epithelial lipid accumulation, microvilli morphologic changes, and decreased tear production were associated with marked declines in PPARα, CPT1α, and TRPV6 expression levels as well as Ezrin phosphorylation status, whereas meibomian glands were unaltered in SDE mice. These effects of SDE mice mimicked those in their nonstressed PPARα-/-counterpart. Topical application of fenofibrate reversed these effects in SDE corneas. In cultured corneal epithelial sheets, fenofibrate increased PPARα and TRPV6 gene and protein expression levels and restored microvilli morphology, whereas MK886 attenuated these changes.

Conclusions: Sleep deprivation induces dry eye through abnormal SCEC microvilli morphology, which is caused by sequential downregulation of PPARα, TRPV6 expression, and Ezrin phosphorylation status in mice.
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http://dx.doi.org/10.1167/iovs.18-24504DOI Listing
November 2018

Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.

Mol Autism 2018 13;9:64. Epub 2018 Dec 13.

1Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.

Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent.

Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes.

Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (), one novel gene with recurrent LGD DNMs (), as well as genes associated with macrocephaly ( and ). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes.

Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk.
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http://dx.doi.org/10.1186/s13229-018-0247-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293633PMC
January 2019

Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders.

Am J Med Genet A 2018 12 9;176(12):2668-2676. Epub 2018 Dec 9.

Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

SHANK3 has been identified as the causative gene of 22q13.3 microdeletion syndrome phenotype. De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome-like phenotype, and intellectual disability (ID). Although broad developmental phenotypes of these patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with SHANK3 DNMs. In this study, we identified a de novo splice mutation (NM_033517.1: c.2265+1G>A) that functionally impairs mRNA splicing, produces multiple splice variants, and results in the reduction of the amounts of mRNA. To analyze the genotype and phenotype correlations for SHANK3 DNMs, we reviewed 37 previously published patients with 28 SHANK3 DNMs. Our results revealed that haploinsufficiency of SHANK3 causes a broad spectrum of neurodevelopmental phenotypes with impaired social interaction, repetitive behavior, speech impairment, ID, and regression as the most common observations. Seizures, hypotonia, global development delay, dysmorphic features, and several other features also occurred recurrently. Specific phenotypes are also observed in certain genotypes. Our study provides the frequency of the heterogeneous co-occurring conditions caused by SHANK3 DNMs, which will be beneficial for diagnosis and clinical management.
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http://dx.doi.org/10.1002/ajmg.a.40666DOI Listing
December 2018
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