Publications by authors named "Ting Guo"

409 Publications

MicroRNA-135b/CAMK2D Axis Contribute to Malignant Progression of Gastric Cancer through EMT Process Remodeling.

Int J Biol Sci 2021 10;17(8):1940-1952. Epub 2021 May 10.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital, Fu-Cheng Road, Beijing, 100142, China.

There is a continued need for investigating the roles of microRNAs (miRNAs) and their targets on the progression of gastric cancer (GC), especially metastasis. Here, we performed an integrated study to identify dysregulated miRNAs critical for GC development and progression. miR-135b was determined as a promising biomarker for GC. The expression level of miR-135b was increased among GC cell lines, patient tumor tissues, serum samples, and correlation with aggravation of the GC patients. The functional assays demonstrated overexpression of miR-135b promoted cell proliferation, migration and invasion in GC, while miR-135b inhibition led to the opposite results. CAMK2D was found to be the direct target of miR-135b, serving as a tumor suppressor in GC cells. Based on our and public datasets, we confirmed the attenuation of CAMK2D expression in GC tissues. And, the expression levels of miR-135b and CAMK2D were closely associated with prognosis of GC patients. Ectopic expression of miR-135b resulted in the down-regulation of CAMK2D. Additionally, CAMK2D was a prerequisite for miR-135b to promote GC cells proliferation and migration by regulating the EMT process, which was confirmed by the experiments. Importantly, injection of miR-135b antagomir significantly repressed the tumor growth and metastasis of xenograft models, which suggested that the miR-135b antagomir were promising for clinical applications. Taken together, these results indicate that miR-135b/CAMK2D axis drives GC progression by EMT process remodeling, suggesting that miR-135b may be utilized as a new therapeutic target and prognostic marker for GC patients.
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http://dx.doi.org/10.7150/ijbs.58062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193265PMC
May 2021

Cofilin-1 promotes fibrocyte differentiation and contributes to pulmonary fibrosis.

Biochem Biophys Res Commun 2021 Aug 2;565:43-49. Epub 2021 Jun 2.

Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central-South University, Changsha, Hunan, China; Research Unit of Respiratory Disease, Central-South University, Changsha, Hunan, China; The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, China. Electronic address:

Fibrocytes originate from the bone marrow monocyte lineage and participate in the pathogenesis of pulmonary fibrosis. Research providing a comprehensive picture of fibrocytes is still limited. Cofilin-1 (CFL-1) is an important protein that regulates cell proliferation, migration and differentiation. Whether CFL-1 can induce monocyte differentiation into fibrocytes and promote the process of pulmonary fibrosis is unknown. Compared with that of healthy controls, the expression of CFL-1 was significantly increased in the plasma and peripheral blood mononuclear cells (PBMCs) from idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD) patients (P < 0.05). The percentages of peripheral blood fibrocytes in the IPF group (4.2550 ± 0.3483%) and CTD-ILD group (4.7100 ± 0.4811%) were higher than that in the control group (1.6340 ± 0.2549%) (both P < 0.05). In vitro, PBMCs transfected with siRNA-CFL-1 showed lower expression of CFL-1, and the percentage of fibrocytes was lower than that of the control (P < 0.05). PBMCs transfected with Lv-CFL-1 to increase the expression of CFL-1 showed a higher percentage of fibrocytes than the control (P < 0.05). In mice with bleomycin-induced pulmonary fibrosis, the relative expression of CFL-1 was increased, and the percentage of fibrocytes was higher than that in the saline group (P < 0.05). In bleomycin-induced mice, interference with Lv-CFL-1 decreased the expression of CFL-1, the percentage of fibrocytes was lower, and the lung tissue showed less fibrosis (P < 0.05). The overexpression of CFL-1 is associated with pulmonary fibrogenesis. CFL-1 could promote the differentiation of fibrocytes from monocyte peripheral blood mononuclear cells and promote pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.085DOI Listing
August 2021

δ-Tocotrienol induces apoptosis and inhibits proliferation of nasopharyngeal carcinoma cells.

Food Funct 2021 May 31. Epub 2021 May 31.

Laboratory of Molecular Nutrition, College of Food Science and Engineering, National Engineering Laboratory for Deep Processing of Rice and Byproducts, Central South University of Forestry and Technology, Changsha, Hunan 410004, China.

Nasopharyngeal carcinoma has a notably high incidence rate in Southern China, Southeast Asia, North Africa, Middle East, and the Arctic. δ-Tocotrienol is abundant in cereal and has some health benefits. In our recent study, we showed that δ-tocotrienol exerted anti-inflammatory effects in murine macrophages in vitro. The aim of this study was to further investigate the chemopreventive effects of δ-tocotrienol on human CNE1 cells. We showed that δ-tocotrienol induced apoptosis and cell cycle arrest at G0/G1 and M phases in nasopharyngeal carcinoma cells. Microarray analysis revealed that after CNE1 cells were treated with δ-tocotrienol, 169 genes were up-regulated and 167 down-regulated. ERK1/2 was shown to play a vital role in cell cycle arrest by gene chips. The results suggest that δ-tocotrienol induces cell cycle arrest in CNE1 cells via the p16/CDK4/cyclin D1 signaling pathway. Western blots showed that CNE1 apoptosis was related to dysregulated expression of Bax-2 and Bcl-2. Furthermore, caspase-3, -8, -9 up-regulation was related to the apoptotic effect of δ-tocotrienol; therefore, δ-tocotrienol triggers apoptosis in CNE1 cells through caspase-3 signaling. δ-Tocotrienol may potentially be developed as an anti-cancer agent in the management of nasopharyngeal carcinoma.
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http://dx.doi.org/10.1039/d1fo00461aDOI Listing
May 2021

Curcumin ameliorates ischemic stroke injury in rats by protecting the integrity of the blood-brain barrier.

Exp Ther Med 2021 Jul 19;22(1):783. Epub 2021 May 19.

Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.

The blood-brain barrier (BBB) is critical for proper cerebral homeostasis and its dysfunction during ischemic stroke can result in significant neurological injury. The major goal of the present study was to identify whether curcumin pretreatment possessed protective effects on BBB integrity during the 24 h of acute ischemic brain injury. To investigate the protective effects of curcumin, male Sprague-Dawley rats were divided into multiple groups, including sham, middle cerebral artery occlusion/reperfusion (MCAO/R) vehicle and curcumin pretreated MCAO/R groups. The effects of curcumin were measured by analyzing neurological deficits, infarct size, BBB permeability and expression levels of permeability-related proteins in the brain. It was found that curcumin pretreatment significantly improved neurological scores, decreased infarct size, and protected synaptic remodeling of hippocampal neurons and upregulated the protein expression level of tight junction proteins, ZO-1, occludin and claudin-5 in ischemic rat brains. Furthermore, curcumin pretreatment before stroke was shown to downregulate the phosphorylation of NF-κB and MMP-9, which are central mediators of inflammation. The results from the present study indicated that curcumin pretreatment ameliorated ischemic stroke injury by protecting BBB integrity and synaptic remodeling, as well as inhibiting inflammatory responses.
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http://dx.doi.org/10.3892/etm.2021.10215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145684PMC
July 2021

A facile aptasensor based on polydopamine nanospheres for high-sensitivity sensing of T-2 toxin.

Anal Methods 2021 May 26. Epub 2021 May 26.

Ministry of Education, College of Food Science, Southwest University, Chongqing 400715, P. R. China. and Medical College, Nankai University, Tianjin 300457, P. R. China.

A facile fluorescent aptasensor based on polydopamine nanospheres (PDANSs) has been proposed for the rapid and high sensitive sensing of T-2 toxin. PDANSs are dopamine-derived synthetic eumelanin polymers with excellent fluorescence quenching ability, dispersibility and biocompatibility. In the assay, 6-carboxyfluorescein (FAM)-labeled aptamers (FAM-aptamers) were adsorbed onto PDANSs via noncovalent bonding, resulting in quenching fluorescence. In the presence of T-2, the binding of T-2 to the aptamers could promote the formation of the A-form duplex hairpin structure, which was used as a sensing platform to detect T-2 on the basis of fluorescence recovery. The results showed that the aptasensor was rapid and sensitive for the detection of T-2 toxin with a linear detection range of 10-180 μg L-1 and a detection limit of 7.23 μg L-1. The performance of the proposed method was comparable with that of the liquid chromatography-mass spectrometry method (LC-MS). Thus, the aptasensor could be used for the determination of real samples. The design method proposed in this study provides a strategy for the development of PDANS-based toxin biosensors.
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http://dx.doi.org/10.1039/d1ay00642hDOI Listing
May 2021

Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial.

Signal Transduct Target Ther 2021 05 17;6(1):194. Epub 2021 May 17.

Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood C and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.
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http://dx.doi.org/10.1038/s41392-021-00603-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127508PMC
May 2021

Effect of temperature and pH on the conversion between free and hidden zearalenone in zein.

Food Chem 2021 Oct 4;360:130001. Epub 2021 May 4.

College of Food Science, Southwest University, Chongqing 400715, PR China; Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, Chongqing 400715, PR China; Biological Science Research Center, Southwest University, Chongqing 400715, PR China. Electronic address:

Food processing might induce the transformation of hidden ZEN (zein-bound ZEN) in maize. The objective of this study was to assess the effect of processing factors on free ZEN and hidden ZEN. After zein was treated under different temperature and pH, ZEN was quantified in samples before and after in vitro digestion. The ratios of hidden to total ZEN in zein are decreased from 54.25% to 40.74% after thermal treatment and from 54.25% to 0 after alkaline treatment, respectively. Conversely, acid treatment increased the ratio of hidden to total ZEN from 54.25% to 100%. Thus, it can be concluded that thermal or alkaline condition induced the conversion of hidden ZEN to free ZEN while acid condition promoted the ZEN-zein interactions to form the hidden ZEN. Overall, temperature and pH values played a vital role in the conversion of hidden ZEN during food processing.
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http://dx.doi.org/10.1016/j.foodchem.2021.130001DOI Listing
October 2021

Design, synthesis and evaluation of novel 9-arylalkyl-10-methylacridinium derivatives as highly potent FtsZ-targeting antibacterial agents.

Eur J Med Chem 2021 Oct 28;221:113480. Epub 2021 Apr 28.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China. Electronic address:

With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound 15f showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, 15f showed no inhibitory effect on Gram-negative bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that 15f functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that 15f not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.
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http://dx.doi.org/10.1016/j.ejmech.2021.113480DOI Listing
October 2021

Dynamics of a new HIV model with the activation status of infected cells.

J Math Biol 2021 04 15;82(6):51. Epub 2021 Apr 15.

Department of Mathematics, University of Florida, Gainesville, FL, 32611, USA.

The activation status can dictate the fate of an HIV-infected CD4+ T cell. Infected cells with a low level of activation remain latent and do not produce virus, while cells with a higher level of activation are more productive and thus likely to transfer more virions to uninfected cells during cell-to-cell transmission. How the activation status of infected cells affects HIV dynamics under antiretroviral therapy remains unclear. We develop a new mathematical model that structures the population of infected cells continuously according to their activation status. The effectiveness of antiretroviral drugs in blocking cell-to-cell viral transmission decreases as the level of activation of infected cells increases because the more virions are transferred from infected to uninfected cells during cell-to-cell transmission, the less effectively the treatment is able to inhibit the transmission. The basic reproduction number [Formula: see text] of the model is shown to determine the existence and stability of the equilibria. Using the principal spectral theory and comparison principle, we show that the infection-free equilibrium is locally and globally asymptotically stable when [Formula: see text] is less than one. By constructing Lyapunov functional, we prove that the infected equilibrium is globally asymptotically stable when [Formula: see text] is greater than one. Numerical investigation shows that even when treatment can completely block cell-free virus infection, virus can still persist due to cell-to-cell transmission. The random switch between infected cells with different activation levels can also contribute to the replenishment of the latent reservoir, which is considered as a major barrier to viral eradication. This study provides a new modeling framework to study the observations, such as the low viral load persistence, extremely slow decay of latently infected cells and transient viral load measurements above the detection limit, in HIV-infected patients during suppressive antiretroviral therapy.
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http://dx.doi.org/10.1007/s00285-021-01604-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049625PMC
April 2021

Increase in arsenic methylation and volatilization during manure composting with biochar amendment in an aeration bioreactor.

J Hazard Mater 2021 06 13;411:125123. Epub 2021 Jan 13.

Institute of Soil and Water Resources and Environmental Science, College of Environmental and Resource Sciences, Zhejiang Provincial Key Laboratory of Agricultural Resources and Environment, Zhejiang University, Hangzhou 310058, China.

Biochar is widely used as an amendment to optimize the composting process. In this study, we firstly investigated the effects of biochar amendment on methylation and volatilization of arsenic (As), and the microbial communities during manure composting. Biochar amendment was found to increase the concentrations of monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) during mesophilic (days 0-10) and early thermophilic (days 11-15) phases, and promote As volatilization during the maturing phase (days 60-80) of composting. In addition, the abundances of As(V) reductase (arsC) and As(III) S-adenosyl-L-methionine methyltransferase (arsM) genes were higher in the biochar treatment than that in the control. Moreover, biochar amendment influenced the microbial communities by promoting As methylation and volatilization via Ensifer and Sphingobium carrying arsC genes, and Rhodopseudomonas and Pseudomonas carrying arsM genes. This study emphasized the considerable role of biochar on methylation and volatilization of As during manure composting and provided an overall characterization of the community compositions of arsC and arsM genes during manure composting. It will broaden our insights in As biogeochemical cycle during manure composting with biochar amendment, which will facilitate the regulation of As during manure composting and its application in agricultural soil.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125123DOI Listing
June 2021

A multifunctional near-infrared fluorescent sensing material based on core-shell upconversion [email protected] nanoparticles and molecularly imprinted polymers for detection of deltamethrin.

Mikrochim Acta 2021 Apr 15;188(5):165. Epub 2021 Apr 15.

College of Food Science, Southwest University, Chongqing, 400716, China.

The construction of multifunctional sensors has attracted considerable attention due to their multifunctional properties, such as high sensitivity and rapid detection. Herein, near-infrared multifunctional fluorescent sensing materials based on core-shell upconversion [email protected] nanoparticle and molecularly imprinted polymers were synthesized for rapid detection of deltamethrin. The difunctional core-shell upconversion [email protected] nanoparticle was introduced as the optical signal and rapid separator. Firstly, the difunctional core-shell materials were prepared through solvothermal method. Then, molecularly imprinted polymers (MIPs) as recognition elements for deltamethrin were coated on the surface of upconversion [email protected] nanoparticle through polymerization. The structure and recognition characterizations of multifunctional fluorescent sensing materials were evaluated. Under optimal condition, the imprinting factor of sensing materials was 3.63, and the fluorescence intensity of sensing materials decreased linearly with increasing concentration of deltamethrin from 0.001 to 1 mg L with a detection limit of 0.749 μg L, and a relative standard deviation of 3.10% was obtained with 5 mg L deltamethrin. The sensing materials showed a high selectivity and were successfully utilized for the detection of deltamethrin in grapes and cabbages; the results showed that the recoveries for two samples obtained were 95.6-102% and 91.8-105%.
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http://dx.doi.org/10.1007/s00604-021-04811-3DOI Listing
April 2021

"Olfactory three-needle" acupuncture enhances synaptic function in Aβ-induced Alzheimer's disease via activating PI3K/AKT/GSK-3β signaling pathway.

J Integr Neurosci 2021 Mar;20(1):55-65

College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine, 712046 Xianyang, P. R. China.

Synaptic dysfunction and neuronal loss are related to cognitive impairment of Alzheimer's disease. Recent evidence indicates that regulating the phosphatidylinositol 3-Kinase (PI3K)/AKT/GSK-3β pathway is a therapeutic strategy for improving synaptic plasticity in Alzheimer's disease. Here, we investigated "olfactory three-needle" effects on synaptic function and the PI3K/AKT/GSK-3β signaling pathway in β-amyloid (Aβ)-induced Alzheimer's disease rats. A three-needle olfactory bulb insertion for 28 days alleviated Aβ-induced Alzheimer's disease rats' cognitive impairment as assessed by performance in the Morris water maze test. Furthermore, the three-needle electrode inhibited neuro-apoptosis and neuro-inflammation. It significantly upregulated the protein expression of postsynaptic density protein 95, synaptophysin, and GAP43, indicating a protective effect on hippocampal synaptic plasticity. Additionally, the activation level of PI3K/AKT signaling and the phosphorylation inactivation of GSK-3β were significantly enhanced by the "olfactory three-needle". Our findings suggested that the three-needle acupuncture is a potential alternative to improve synaptic plasticity and neuronal survival of Alzheimer's disease brain in rodents.
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http://dx.doi.org/10.31083/j.jin.2021.01.224DOI Listing
March 2021

COLGALT2 is overexpressed in ovarian cancer and interacts with PLOD3.

Clin Transl Med 2021 Mar;11(3):e370

Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People's Republic of China.

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http://dx.doi.org/10.1002/ctm2.370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989968PMC
March 2021

Meiotic Recombination Defects and Premature Ovarian Insufficiency.

Front Cell Dev Biol 2021 8;9:652407. Epub 2021 Mar 8.

Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.

Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1-5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20-25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women.
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http://dx.doi.org/10.3389/fcell.2021.652407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982532PMC
March 2021

Case Report: Identification of a Novel Variant in a Patient With Primary Ciliary Dyskinesia.

Front Genet 2021 26;12:652381. Epub 2021 Feb 26.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.

encodes a protein of 595 amino acids and contain three highly conserved coiled-coil domains, which is essential for cilia axoneme dynein arm assembly and docking. Primary ciliary dyskinesia (PCD) of deficiency are rarely reported. Female infertility in PCD related to variants has not been reported. Whole-exome and Sanger sequencing were used to identify the disease-related gene of the patient with PCD in a consanguineous Chinese family. Domain analysis was applied to predict the impact of the variant on ODAD3 protein. The 35 year-old female patient exhibited chronic sinusitis, diffuse bronchiectasis, dextrocardia and infertility. We identified a novel homozygous variant in , c.1166_1169dupAGAC, p.(Leu391Aspfs105) in the PCD patient by exome sequencing and Sanger sequencing. This frameshift variant was predicted to be disease causing by bioinformatics analysis and was also not presented in the current authorized large genetic databases. Our study enriches the genetic spectrum and clinical phenotypes of variants in PCD and provide more evidence for future genetic counseling and gene-targeted therapy for this disease.
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http://dx.doi.org/10.3389/fgene.2021.652381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953140PMC
February 2021

Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice.

J Exp Med 2021 May;218(5)

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL.

Aging is a strong risk factor and an independent prognostic factor for progressive human idiopathic pulmonary fibrosis (IPF). Aged mice develop nonresolving pulmonary fibrosis following lung injury. In this study, we found that mouse double minute 4 homolog (MDM4) is highly expressed in the fibrotic lesions of human IPF and experimental pulmonary fibrosis in aged mice. We identified MDM4 as a matrix stiffness-regulated endogenous inhibitor of p53. Reducing matrix stiffness down-regulates MDM4 expression, resulting in p53 activation in primary lung myofibroblasts isolated from IPF patients. Gain of p53 function activates a gene program that sensitizes lung myofibroblasts to apoptosis and promotes the clearance of apoptotic myofibroblasts by macrophages. Destiffening of the fibrotic lung matrix by targeting nonenzymatic cross-linking or genetic ablation of Mdm4 in lung (myo)fibroblasts activates the Mdm4-p53 pathway and promotes lung fibrosis resolution in aged mice. These findings suggest that mechanosensitive MDM4 is a molecular target with promising therapeutic potential against persistent lung fibrosis associated with aging.
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http://dx.doi.org/10.1084/jem.20202033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953267PMC
May 2021

Integrated multi-spectroscopic and molecular modeling techniques to study the formation mechanism of hidden zearalenone in maize.

Food Chem 2021 Jul 15;351:129286. Epub 2021 Feb 15.

College of Food Science, Southwest University, Chongqing 400715, PR China; Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, Chongqing 400715, PR China; Biological Science Research Center, Southwest University, Chongqing 400715, PR China. Electronic address:

Hidden mycotoxins have been reported to be "protected" by macromolecular substances to escape routine determination, but release to free mycotoxins under gastrointestinal conditions. Nowadays, the hidden zearalenone (ZEN) that binding with macromolecular zein has been found in maize. However, the binding mechanism of ZEN with zein in maize has not been clarified. In this study, the formation of ZEN-zein complex was investigated applying ultrafiltration, multi-spectroscopic and molecular modeling techniques. The steady-state and transient fluorescence analysis suggested the ZEN could interact with zein to form the complex driven by hydrophobic force and hydrogen bonds, which is in accordance with the molecular modeling studies. The conformational changes of zein induced by binding with ZEN were revealed by Fourier transform infrared spectroscopy (FTIR) and circular dichroism (CD). Elucidating the binding mechanism between zein and ZEN could help the development of detecting hidden ZEN and guarantee the safety of maize products.
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http://dx.doi.org/10.1016/j.foodchem.2021.129286DOI Listing
July 2021

Paeoniflorin alleviates endothelial dysfunction caused by overexpression of soluble fms-like tyrosine kinase 1 and soluble endoglin in preeclampsia via VEGFA upregulation.

Biosci Biotechnol Biochem 2021 Mar;85(4):814-823

The Second Department of Obstetrics, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, China.

This study assessed the protective effects of paeoniflorin against preeclampsia-related endothelial damage (ED). Human umbilical vein endothelial cells (HUVECs) isolated from healthy puerperae were identified by immunofluorescence assay. After paeoniflorin treatment, HUVECs were induced by soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) to establish ED. Cell viability, migration, invasion, tube formation, and apoptosis were assessed by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium MTT assay, Scratch assay, Transwell assay, tube formation assay, and flow cytometry. VEGFA expression in HUVECs was analyzed by Western blot. HUVECs were successfully isolated and identified as Von Willebrand factor (vWF) positive. Individual treatment or cotreatment of sFlt-1 and sEng inhibited migration, invasion and tube formation, enhanced apoptosis, and decreased VEGFA expression in HUVECs. Paeoniflorin pretreatment partially reversed the effects delivered by cotreatment of sFlt-1 and sEng in HUVECs. Paeoniflorin alleviated preeclampsia-related ED caused by overexpression of sFlt-1 and sEng by upregulating VEGFA.
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http://dx.doi.org/10.1093/bbb/zbaa106DOI Listing
March 2021

Insulin gene enhancer protein 1 mediates glycolysis and tumorigenesis of gastric cancer through regulating glucose transporter 4.

Cancer Commun (Lond) 2021 Mar 11;41(3):258-272. Epub 2021 Feb 11.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China.

Background: Insulin gene enhancer protein 1, (ISL1), a LIM-homeodomain transcription factor, is involved in multiple tumors and is associated with insulin secretion and metabolic phenotypes. However, the role of ISL1 in stimulating glycolysis to promote tumorigenesis in gastric cancer (GC) is unclear. In this study, we aimed to characterize the expression pattern of ISL1 in GC patients and explore its molecular biological mechanism in glycolysis and tumorigenesis.

Methods: We analyzed the expression and clinical significance of ISL1 in GC using immunohistochemistry and real-time polymerase chain reaction (PCR). Flow cytometry and IncuCyte assays were used to measure cell proliferation after ISL1 knockdown. RNA-sequencing was performed to identify differentially expressed genes, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA) to reveal key signaling pathways likely regulated by ISL1 in GC. Alteration of the glycolytic ability of GC cells with ISL1 knockdown was validated by measuring the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) and by detecting glucose consumption and lactate production. The expression of glucose transporter 4 (GLUT4) and ISL1 was assessed by Western blotting, immunohistochemistry, and immunofluorescent microscopy. The luciferase reporter activity and chromatin immunoprecipitation assays were performed to determine the transcriptional regulation of ISL1 on GLUT4.

Results: High levels of ISL1 and GLUT4 expression was associated with short survival of GC patients. ISL1 knockdown inhibited cell proliferation both in vitro and in vivo. KEGG analysis and GSEA for RNA-sequencing data indicated impairment of the glycolysis pathway in GC cells with ISL1 knockdown, which was validated by reduced glucose uptake and lactate production, decreased ECAR, and increased OCR. Mechanistic investigation indicated that ISL1 transcriptionally regulated GLUT4 through binding to its promoter.

Conclusion: ISL1 facilitates glycolysis and tumorigenesis in GC via the transcriptional regulation of GLUT4.
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http://dx.doi.org/10.1002/cac2.12141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968886PMC
March 2021

Clinical Findings in Diabetes Mellitus Patients with COVID-19.

J Diabetes Res 2021 8;2021:7830136. Epub 2021 Jan 8.

Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central-South University, Changsha, Hunan 410011, China.

Backgrounds: Diabetes mellitus (DM) is one of the most common comorbidities in patients with coronavirus disease (COVID-19). We aim to summarize the clinical features of DM patients with COVID-19 and find out potential factors associated with severe disease.

Methods: In this retrospective, single-center study, the medical records of patients with COVID-19 in Changsha, Hunan, China, from January 21, 2020, to February 19, 2020, were reviewed. Epidemiological information, clinical features, and outcomes were compared between DM patients admitted to the intensive care unit (ICU) or not.

Results: A total of 241 patients confirmed with COVID-19 were enrolled, including 19 DM patients. There were more patients in DM group admitted to the ICU than non-DM group (36.8% vs. 15.8%, = 0.045). Compared with non-DM group in the ICU, there were more female patients from DM group in the ICU (85.7% vs. 31.4%, = 0.024). On admission, the mean level of glycated hemoglobin A1c (HbA1c) was higher in the ICU DM patients than that in the non-ICU DM patients (8.5% vs. 7.1%). There were more DM patients with proteinuria in the ICU group than the non-ICU group (57.1% vs. 33.3%). Twelve DM patients (63.2%) changed diabetic therapy during hospitalization, and all DM patients admitted to the ICU used insulin. As of March 14, all 19 DM patients have been discharged, and no death occurred.

Conclusions: DM patients with COVID-19 are vulnerable to severe disease, especially for female patients. High levels of HbA1c and proteinuria could be potential risk factors for severe COVID-19 in DM patients. In addition to timely systemic therapy, the control of blood glucose and proper diabetic therapy is essential to improve the prognosis of severe DM patients with COVID-19.
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http://dx.doi.org/10.1155/2021/7830136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811569PMC
February 2021

Epigenetic Alteration Shaped by the Environmental Chemical Bisphenol A.

Front Genet 2020 11;11:618966. Epub 2021 Jan 11.

Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Bisphenol A (BPA) is extensively used in plastic products and epoxy resins. The epigenetic response to the environmental chemical BPA was involved in multiple dysfunctional categories, such as cancer, the reproductive system, metabolism, pubertal development, peripheral arterial disease, infant and childhood growth, and neurodevelopment outcomes. In this mini-review, we described the recent progress of the epigenetic effects of the environmental chemical BPA, including DNA methylation, histone methylation, and toxic epigenomics. Notably, the histone modification changes under BPA exposure are summarized in this review. DNA methylation accompanied by transcriptional changes in key genes affected by BPA exposure is related to various processes, including neural development, cancer pathways, and generational transmission. In addition, BPA could also affect histone modifications in many species, such as humans, rats, and zebrafish. Finally, we reviewed recent studies of the toxico-epigenomics approach to reveal the epigenetic effect of BPA exposure genome-wide.
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http://dx.doi.org/10.3389/fgene.2020.618966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830874PMC
January 2021

Clinicopathological and Immunomicroenvironment Characteristics of Epstein-Barr Virus-Associated Gastric Cancer in a Chinese Population.

Front Oncol 2020 8;10:586752. Epub 2021 Jan 8.

Department of Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.

Background: Epstein-Barr virus-associated gastric cancer(EBVaGC)has a unique tumor immune microenvironment. We performed a comprehensive analysis of the tumor-infiltrating immune cells in a cohort of EBVaGC in a Chinese population.

Methods: Epstein-Barr encoding region (EBER) hybridization was performed in 1,328 consecutive cases of surgically resected GC. Densities of immune cells, including T cells, B cells, natural killer cells, and macrophages from the patients were calculated after immunohistochemical staining with CD3, CD20, CD57, and CD68 antibodies in tissue microarrays, respectively.

Results: EBVaGC patients accounted for 4.1% (55 of 1,328) cases in the overall population. The average age of patients with EBVaGC was lower than that of non-EBVaGC patients. Histologically, EBVaGC patients exhibited poorly differentiated adenocarcinoma (P = 0.004) and lower frequency of vascular invasion (P = 0.034). The density of CD3 T lymphocytes (CD3, 23.84 ± 14.49 12.76 ± 8.93, P < 0.001) and CD68 macrophages (CD68, 9.73 ± 5.25 5.44 ± 4.18, P < 0.001) was significantly higher in EBVaGC patients. CD3 T cell density predicted better 5-year overall survival of EBVaGC patients (P = 0.022).

Conclusions: EBVaGC patients were younger with low-differentiated adenocarcinoma and less vascular invasion. Increased infiltration of multiple immune cells affected the prognosis of patients, especially EBVaGC patients with more CD3 T lymphocytes, who survived longer.
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http://dx.doi.org/10.3389/fonc.2020.586752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820894PMC
January 2021

PLODs are overexpressed in ovarian cancer and are associated with gap junctions via connexin 43.

Lab Invest 2021 May 22;101(5):564-569. Epub 2021 Jan 22.

Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Rd, Shanghai, 200011, PR China.

Procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) play important roles in cancer progression, but their role in ovarian cancer remains elusive. In silico analysis of expression of PLODs in ovarian cancer was performed with reproduction of The Cancer Genome Atlas dataset. PLOD-enriched pathways and related gene(s) were validated by immunohistochemistry (IHC) in 80 ovarian cancer tissue blocks and in vivo xenograft murine models. PLODs (PLOD-1, -2, and -3) were overexpressed in ovarian cancer tissue. Overexpression of individual PLODs showed mutual exclusivity. Each of the three PLODs was differentially expressed between normal and cancer tissue of the ovary. PLOD1 was not prognostic, whereas lower PLOD2 and higher PLOD3 expression were associated with worsened prognosis, respectively. Cases with PLOD overexpression showed enrichment in gap junctions. GJA1 (connexin 43) was significantly overexpressed in cases with PLOD overexpression. IHC in tissue showed the strongest positive correlation between PLOD3 and connexin 43 expression, followed by PLOD2. As per Harmonizome, we selected SKOV3 and CAOV3 cell lines based on constitutive high PLOD1 and PLOD2/PLOD3 expression, respectively for in vitro and in vivo modeling. Only knockdown of PLOD3 was significantly associated with decreased GJA1 expression level in both cell lines. IHC in murine xenograft tumors also showed significantly lower connexin 43 in PLOD3-KD SKOV3 tumors. We conclude that PLODs are generally overexpressed in ovarian cancer and each PLOD may be functionally non-redundant. Association between PLOD3 and gap junctions warrants further investigation.
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http://dx.doi.org/10.1038/s41374-021-00533-5DOI Listing
May 2021

MiR-103-3p targets the m A methyltransferase METTL14 to inhibit osteoblastic bone formation.

Aging Cell 2021 02 13;20(2):e13298. Epub 2021 Jan 13.

Department of Orthopedics, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR-103-3p was found to be negatively correlated with bone formation in bone specimens from elderly women with fractures and ovariectomized (OVX) mice. Additionally, miR-103-3p directly targeted Mettl14 to inhibit osteoblast activity, and METTL14-dependent N -methyladenosine (m A) methylation inhibited miR-103-3p processing by the microprocessor protein DGCR8 and promoted osteoblast activity. Moreover, miR-103-3p inhibited bone formation in vivo, and therapeutic inhibition of miR-103-3p counteracted the decreased bone formation in OVX mice. Further, METTL14 was negatively correlated with miR-103-3p but positively correlated with bone formation in bone specimens from elderly women with fractures and OVX mice. Collectively, our results highlight the critical roles of the miR-103-3p/METTL14/m A signaling axis in osteoblast activity, identifying this axis as a potential target for ameliorating osteoporosis.
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http://dx.doi.org/10.1111/acel.13298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884043PMC
February 2021

Application of membrane separation processes in phosphorus recovery: A review.

Sci Total Environ 2021 May 29;767:144346. Epub 2020 Dec 29.

Southeast University, School Energy & Environment, 2 Sipailou Rd, Nanjing 210096, PR China; ERC Taihu Lake Water Environment Wuxi, 99 Linghu Rd, Wuxi 214135, PR China. Electronic address:

The depletion of phosphorus resources and the excess discharge of phosphorus into waste streams are contrasting problems. The key to solving both problems is to recover phosphorus from the waste streams. Current phosphorus recovery technologies require high phosphorus concentrations and lack the ability to separate toxic substances from recovered phosphorus products. Membrane separation processes such as nanofiltration, forward osmosis, and electrodialysis are examples of effective methods for solving some of these issues. In this paper, the mechanisms, performance, and influential factors affect phosphorus recovery from membrane separation are reviewed. Membrane fouling, energy consumption, and the selectivity of toxic substances in membrane separation processes were evaluated. This work will serve as a basis for future research and development of phosphorus recovery by membrane separation processes and as a response to the increasingly pressing issues of eutrophication and the growing depletion of phosphorus resources.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144346DOI Listing
May 2021

Platelet‑derived growth factor‑BB mediates pancreatic cancer malignancy via regulation of the Hippo/Yes‑associated protein signaling pathway.

Oncol Rep 2021 01 19;45(1):83-94. Epub 2020 Nov 19.

Department of Transplantation, The Second Affiliated Hospital of Hainan Medical University, Transplantation Institute of Hainan Medical University, Haikou, Hainan 570105, P.R. China.

Platelet‑derived growth factor (PDGF) is a potent mitogen and chemoattractant that serves a role in the development of several types of solid cancer, and abnormal PDGF activity has been reported in numerous human tumors. Tumor‑derived PDGF ligands are considered to act in either a paracrine or autocrine manner, serving roles in the phosphorylation of receptors on tumor and stromal cells in the tumor microenvironment. Despite the well‑established association between PDGF and tumor progression, the precise mechanisms of autocrine PDGF signaling in pancreatic tumor cells remain elusive. Therefore, the present study aimed to analyze the influence of PDGF‑BB in pancreatic cancer. Pancreatic adenocarcinoma BxPC‑3 cells were cultured and treated with recombinant human PDGF‑BB in vitro. Cell proliferation was tested using an MTT assay. Cell apoptosis was measured using flow cytometry. Tumor cell migration and invasion were examined via wound‑healing and Transwell assays, respectively. The expression and subcellular localization of Yes‑associated protein (YAP) was determined using western blotting and immunofluorescence. The transcriptional activity of target genes was tested using a luciferase assay and reverse transcription‑quantitative PCR. The present study revealed that PDGF‑BB significantly promoted cell proliferation in pancreatic adenocarcinoma BxPC‑3 cells and enhanced the aggressiveness of this cell line, as demonstrated by Transwell and wound‑healing assays. Anoikis resistance is an important mechanism by which metastatic cells avoid apoptosis when detaching from adjacent cells or the extracellular matrix. PDGF‑BB treatment inhibited anoikis under anchorage‑independent conditions. Mechanistic experiments revealed that PDGF‑BB promoted the upregulation and activation of the transcriptional coactivator YAP, an effector of the Hippo signaling pathway. RhoA or protein phosphatase‑1 (PP‑1) inhibition partially abolished the accumulation and activation of YAP, suggesting PDGF‑BB‑mediated YAP dephosphorylation and transactivation via the RhoA/PP‑1 cascade. Pharmacologic inhibition of the PDGF receptor directly downregulated YAP activity and the expression levels of downstream genes. Furthermore, verteporfin, a small molecular inhibitor of the Hippo/YAP signaling pathway, partially reversed the effects of PDGF‑BB on cell proliferation, anoikis resistance and cell migration. In conclusion, the present study revealed that the Hippo/YAP signaling pathway may be involved in the tumor‑promoting activity of PDGF‑BB in pancreatic cancer.
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http://dx.doi.org/10.3892/or.2020.7859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709832PMC
January 2021

Upregulation of long noncoding RNA XIST has anticancer effects on ovarian cancer through sponging miR-106a.

Hum Cell 2021 Mar 5;34(2):579-587. Epub 2021 Jan 5.

Emergency Department, Taizhou People's Hospital Affiliated to Nantong University, Taizhou, 225300, Jiangsu, China.

Ovarian cancer (OC) is a highly malignant tumor. X inactive specific transcript (XIST) was identified as a cancer-related gene, while its therapeutic effect in OC was poorly defined. The present study was designed to investigate the effectual corollary of the lncRNA XIST in OC. RT-qPCR was used to detect the XIST and miR-106a expression levels of OC tissues and cell lines. OC cell apoptosis and proliferation were detected by flow cytometry, colony formation, and CCK-8 assays. Moreover, bioinformatics analysis was used to predict the targeted miRNA of XIST. The dual-luciferase reporter and RNA pull-down assays were then used to verify the interaction between miR-106a and XIST. OC xenograft nude mice were raised to measure tumor growth. Notably, OC tissues and cells exhibited low XIST levels and high miR-106a levels. The XIST upregulation decreased the OVCAR3 and CAOV3 cell proliferation and inversely promoted cell apoptosis. miR-106a targeted the XIST. Also, the miR-106a overexpression reversed the inhibitory effects of XIST on OC cell proliferation and apoptosis. Our in vivo results suggested that XIST was involved in tumor growth deceleration, while the miR-106a reversed the effect. To conclusion, the present study demonstrated that XIST suppressed OC development via sponging miR-106a both in vitro and in vivo.
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http://dx.doi.org/10.1007/s13577-020-00469-wDOI Listing
March 2021

Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia.

Hum Genet 2021 May 3;140(5):761-773. Epub 2021 Jan 3.

Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.

Genetics-associated asthenoteratozoospermia is often seen in patients with multiple morphological abnormalities of the sperm flagella (MMAF). Although 24 causative genes have been identified, these explain only approximately half of patients with MMAF. Since sperm flagella and motile cilia (especially respiratory cilia) have similar axonemal structures, many patients with MMAF also exhibit respiratory symptoms, such as recurrent airway infection, chronic sinusitis, and bronchiectasis, which are frequently associated with primary ciliary dyskinesia (PCD), another recessive disorder. Here, exome sequencing was conducted to evaluate the genetic cause in 53 patients with MMAF and classic PCD/PCD-like symptoms. Two homozygous missense variants and a compound-heterozygous variant in the BRWD1 gene were identified in three unrelated individuals. BRWD1 staining was detected in the whole flagella and respiratory cilia of normal controls but was absent in BRWD1-mutated individuals. Transmission electron microscopy and immunostaining demonstrated that BRWD1 deficiency in human affected respiratory cilia and sperm flagella differently, as the absence of outer and inner dynein arms in sperm flagellum and respiratory cilia, while with a decreased number and outer doublet microtubule defects of respiratory cilia. To our knowledge, this is the first report of a BRWD1-variant-related disease in humans, manifesting as an autosomal recessive form of MMAF and PCD/PCD-like symptoms. Our data provide a basis for further exploring the molecular mechanism of BRWD1 gene during spermatogenesis and ciliogenesis.
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http://dx.doi.org/10.1007/s00439-020-02241-4DOI Listing
May 2021

Periphyton enhances arsenic release and methylation at the soil-water interface of paddy soils.

J Hazard Mater 2021 05 24;409:124946. Epub 2020 Dec 24.

Institute of Soil and Water Resources and Environmental Science, Zhejiang Provincial Key Laboratory of Agricultural Resources and Environment, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.

Periphyton is ubiquitous in rice paddy fields, however its role in paddy soil arsenic (As) biogeochemistry remains unexplored. In this study, microcosm incubations and extensive field sampling were used to better understand the roles of periphyton on As mobility and transformation at the soil-water interface. Microcosm incubations revealed that periphyton on the paddy soil surface enhanced As release to water and increased methylated As contents at the soil-water interface. Experimental additions of dissolved phosphate did not significantly affect these processes. The presence of periphyton increased the dissolved organic carbon (DOC) content of the surface soil which may have played a role in the increased As mobility. However, the increase in methylated As species at the soil-water interface is indicative of detoxification processes of As by periphyton. The results from the field study revealed a high abundance and diversity of As biotransformation and detoxification genes in periphyton. Genera of Kineosporia, Limisphaera, Ornatilinea, Ktedonosporobacter and Anaerolinea played key roles in shaping arsM harboring microbe communities in field periphyton. These results highlight the importance of periphyton in the behavior of As in paddy soils and can potentially facilitate improved management of As contamination in paddy soils.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124946DOI Listing
May 2021

Delayed maturation of the structural brain connectome in neonates with congenital heart disease.

Brain Commun 2020 27;2(2):fcaa209. Epub 2020 Nov 27.

Centre for MR Research, University Children's Hospital Zurich, Zurich 8032, Switzerland.

There is emerging evidence for delayed brain development in neonates with congenital heart disease. We hypothesize that the perioperative development of the structural brain connectome is a proxy to such delays. Therefore, we set out to quantify the alterations and longitudinal pre- to post-operative changes in the connectome in congenital heart disease neonates relative to healthy term newborns and assess factors contributing to disturbed perioperative network development. In this prospective cohort study, 114 term neonates with congenital heart disease underwent cardiac surgery at the University Children's Hospital Zurich. Forty-six healthy term newborns were included as controls. Pre- and post-operative structural connectomes were derived from mean fractional anisotropy values of fibre pathways traced using diffusion MR tractography. Graph theory parameters calculated across a proportional cost threshold range were compared between groups by multi-threshold permutation correction adjusting for confounders. Network-based statistic was calculated for edgewise network comparison. White-matter injury volume was quantified on 3D T1-weighted images. Random coefficient mixed models with interaction terms of (i) cardiac subtype and (ii) injury volume with post-menstrual age at MRI, respectively, were built to assess modifying effects on network development. Pre- and post-operatively, at the global level, efficiency, indicative of network integration, was lower in heart disease neonates than controls. In contrast, local efficiency and transitivity, indicative of network segregation, were higher compared to controls (all  < 0.025 for one-sided -tests). Pre-operatively, these group differences were also found across multiple widespread nodes (all  < 0.025, accounting for multiple comparison), whereas post-operatively nodal differences were not evident. At the edge-level, the majority of weaker connections in heart disease neonates compared to controls involved inter-hemispheric connections (66.7% pre-operatively; 54.5% post-operatively). A trend showing a more rapid pre- to post-operative decrease in local efficiency was found in class I cardiac sub-type (biventricular defect without aortic arch obstruction) compared to controls. In congenital heart disease neonates, larger white-matter injury volume was associated with lower strength ( = 0.0026) and global efficiency ( = 0.0097). The maturation of the structural connectome is delayed in congenital heart disease neonates, with a pattern of lower structural integration and higher segregation compared to controls. Trend-level evidence indicated that normalized post-operative cardiac physiology in class I sub-types might improve structural network topology. In contrast, the burden of white-matter injury negatively impacts network strength and integration. Further research is needed to elucidate how aberrant structural network development in congenital heart disease represents neural correlates of later neurodevelopmental impairments.
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http://dx.doi.org/10.1093/braincomms/fcaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756099PMC
November 2020