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1.
PLoS Comput Biol ; 18(9): e1010468, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36095011

RESUMO

Studies comparing single cell RNA-Seq (scRNA-Seq) data between conditions mainly focus on differences in the proportion of cell types or on differentially expressed genes. In many cases these differences are driven by changes in cell interactions which are challenging to infer without spatial information. To determine cell-cell interactions that differ between conditions we developed the Cell Interaction Network Inference (CINS) pipeline. CINS combines Bayesian network analysis with regression-based modeling to identify differential cell type interactions and the proteins that underlie them. We tested CINS on a disease case control and on an aging mouse dataset. In both cases CINS correctly identifies cell type interactions and the ligands involved in these interactions improving on prior methods suggested for cell interaction predictions. We performed additional mouse aging scRNA-Seq experiments which further support the interactions identified by CINS.

2.
Bioresour Technol ; 363: 127883, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36067888

RESUMO

The microbial electrolysis cell coupled the two-phase anaerobic digestion (MEC-TPAD) was developed for simultaneous recovery of bio-sulfur and bio-methane from sulfate-rich wastewater. In acidogenic phase, the produced sulfides were efficiently converted into bio-sulfur via anodic bio-oxidation, with a maximum recovery of 59 ± 5.5 %. The anode coupled acidogenesis produced more volatile fatty acids which were benefit for the subsequent methanogenesis. The cathode in methanogenic phase created a suitable pH condition and enhanced the methanogenesis. Correspondingly, the maximum bio-methane yield in MEC-TPAD was 2 times higher than that in TPAD. Microbial communities revealed that major functional consortia capable of sulfides oxidation (e.g. Alcaligenes) in anode biofilm, hydrogenotrophic methanogenesis (e.g. Methanobacterium) in cathode biofilm, and acetotrophic methanogenesis (e.g. Methanosaeta) in methanogenic sludge were enriched. Economic benefit could totally cover the cost of input electric energy. This work opens an appealing avenue for recovering nutrient and energy from wastewater.

3.
Curr Opin Cell Biol ; 78: 102129, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36126370

RESUMO

Circadian clocks are cell autonomous timekeepers that regulate ∼24-h oscillations in the expression of many genes and control rhythms in nearly all our behavior and physiology. Almost every cell in the human body has a molecular clock and networks of cells containing clock proteins orchestrate daily rhythms in many physiological processes, from sleep-wake cycles to metabolism to immunity. All eukaryotic circadian clocks are based on transcription-translation delayed negative feedback loops in which activation of core clock genes is negatively regulated by their cognate protein products. Our current understanding of circadian clocks has been accumulated from decades of genetic and biochemical experiments, however, what remains poorly understood is how clock proteins, genes, and mRNAs are spatiotemporally organized within live clock cells and how such subcellular organization affects circadian rhythms at the single cell level. Here, we review recent progress in understanding how clock proteins and genes are spatially organized within clock cells over the circadian cycle and the role of such organization in generating circadian rhythms and highlight open questions for future studies.

4.
Front Immunol ; 13: 900963, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119039

RESUMO

Current evidence highlights the critical role of the gut-kidney axis in the pathogenesis of IgA nephropathy (IgAN). However, few attempts have been made to explore targeted intestinal immunity therapy. This research aims to develop an oral intestine targeting medication based on extracellular vesicles (EVs) and investigate its therapeutic efficacy in IgAN. EVs were isolated from orange juice and electroporated with dexamethasone sodium phosphate (DexP). After oral administration, EVs-DexP was picked up by lymphocytes in the submucosal area of ileocecum. EVs-DexP outperformed DexP not only in suppressing lymphocyte stimulation in vitro but also in alleviating renal pathological lesions in the IgAN mouse model. Clinical improvement was accompanied by a reducing IgA secreted by the intestine and a decreasing IgA + B220 + lymphocytes in Peyer's patches. The present study develops a cost-effective, biofriendly EVs-based glucocorticoid strategy for IgAN.


Assuntos
Citrus sinensis , Vesículas Extracelulares , Glomerulonefrite por IGA , Animais , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Vesículas Extracelulares/patologia , Glucocorticoides/uso terapêutico , Imunoglobulina A , Linfócitos/patologia , Camundongos , Proteinúria
5.
J Org Chem ; 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36103134

RESUMO

A mechanistic investigation of α-alkynylation and α-allenylation of aldehydes under the synergistic catalysis of AuCl/amine was performed using density functional theory (DFT) calculations. For such a reaction that delivers two products, this study reveals that the reaction undergoes such a mechanistic mode: reactants → alkynyl product → allenyl product, implying that the allenyl product cannot be obtained directly from reactants. The product ratio obtained experimentally was rationalized based on the computed results that both products can reversibly interconvert with AuCl as the catalyst and with N-containing Lewis bases as additives such as 4,5-diazafluorenone. For the relative stability of alkynyl versus allenyl compounds, unsaturated substituents are found to favor the allenyl compounds.

6.
Infect Agent Cancer ; 17(1): 45, 2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36030232

RESUMO

BACKGROUND: Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important risk factors for hepatocellular carcinoma. However, their effect on other hepatobiliary cancers, such as biliary tract cancers (BTCs), is not well established. We aimed to investigate associations between HBV or HCV infection and BTCs risk by conducting a systematic review and meta-analysis. METHODS: We searched PubMed to identify all relevant articles published before June 9, 2021. Meta-analysis was performed to calculate pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The meta-analysis was evaluated by heterogeneity testing, sensitivity analyses, and publication bias assessment. RESULTS: In total, 48 articles involving 69,723 cases and 4,047,574 controls were obtained to calculate the associations between HBV or HCV infection and the risk of BTCs. We found that both HBV and HCV infections were associated with the risk of BTCs, with pooled ORs of 2.16 (95% CI 1.73-2.69) and 2.12 (95% CI 1.62-2.77), respectively. Subgroup analyses by ethnicity suggested that HBV infection could increase the risk of BTCs in both Asian (OR = 2.29, 95% CI 1.76-2.97) and Caucasian (OR = 1.80, 95% CI 1.18-2.75) populations. In addition, HCV infection resulted in a higher increased risk of BTCs in Caucasian populations than in Asian populations (OR = 3.93 vs. 1.51, P = 0.014). In particular, significantly increased risks of intrahepatic cholangiocarcinoma (ICC) were identified in individuals with HBV (OR = 3.96, 95% CI 3.05-5.15) or HCV infection (OR = 2.90, 95% CI 2.07-4.08). CONCLUSIONS: This study suggests that both HBV and HCV infections are risk factors for BTCs, particularly ICC, highlighting the necessity of cancer screening for BTCs in patients with either HBV or HCV infection.

7.
PeerJ ; 10: e13873, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36032943

RESUMO

Carbon sequestration in forest soil is critical for reducing atmospheric greenhouse gas concentrations and slowing down global warming. However, little is known about the difference in soil organic carbon (SOC) among different stand ages and the relative importance of biotic and abiotic variations such as soil microbial community and soil physicochemical properties in the regulation of SOC in forests. In the present study, we measured the SOC of the topsoil (0-10 cm) in Chinese subtropical Cunninghamia lanceolata plantations of three different stand ages (young plantation of 6 years, middle-aged plantation of 12 years, and mature plantation of 25 years). We further measured microbial community composition by phospholipid fatty acid (PLFA) analysis and soil organic carbon physical fractions by wet sieving and density floating as well as other physicochemical properties. The effects of the main impact factors on SOC were investigated. The results showed that: the middle-aged plantation had significantly higher SOC (10.63 g kg-1) than the young plantation (5.33 g kg-1), and that of the mature plantation (7.83 g kg-1) was in between. Besides, the soil total PLFAs and all the functional groups (i.e., bacteria, fungi, actinomycetes, Gram-positive bacteria, and Gram-negative bacteria) of PLFAs were significantly higher in the middle-aged plantation than in the young plantation and the mature plantation. Soil physicochemical properties, including physical fractions, differed among plantations of the three stand ages. Notably, the proportion of organic carbon protected within microaggregates was significantly higher in the middle-aged plantation (40.4%) than those in the young plantation (29.2%) and the mature plantation (27.8%), indicating that the middle-aged Cunninghamia lanceolata plantation had stronger soil organic carbon stability. Both soil microbial community and physicochemical properties exerted dominant effects on SOC and jointly explained 82.7% of the variance of SOC among different stand ages. Among them, total and all the functional groups of PLFAs, nitrate nitrogen, total nitrogen, and organic carbon protected within microaggregates had a significant positive correlation with SOC. These results highlight the important role of soil biotic and abiotic factors in shaping the contents of SOC in forests of different stand ages. This study provides a theoretical basis for forestry management and forest carbon cycling models.

8.
Front Oncol ; 12: 923683, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992819

RESUMO

Background: Intrathyroid thymic carcinoma (ITTC) is a rare malignancy of the thyroid gland with histological and immunophenotypic resemblance to thymic carcinoma. Surgery combined with adjuvant radiotherapy improves the survival of patients with ITTC. However, for patients with extensive metastases, there is currently no effective treatment. Chemotherapy is an option but has not demonstrated improved patient survival. Methods and results: A female patient presented with metastases to the pleura, lung, and bone 16 years after surgery for ITTC. As radiotherapy and chemotherapy failed to control the recurrent disease, lenvatinib treatment was initiated. After 3 months, positron emission tomography/computed tomography showed a substantial reduction of all metastatic lesions and decreased tumor metabolism. The patient continues to receive lenvatinib and remains well and symptom-free. Conclusion: For patients with ITTC who have progressive, life-threatening metastases, lenvatinib represents a valuable salvage therapy that may offer a sustained reduction in tumor burden and maintenance of quality of life.

9.
Biochem Biophys Res Commun ; 624: 112-119, 2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-35940123

RESUMO

Revealing the organizing principles of developing neural networks is a difficult but significant task in neuroscience. As a creature with a rather compact and well-studied neural network, C. elegans is an ideal subject for neuroscience study. However, the researches on its developing neural network remain challenging. The changes in specific properties of neural network across development may uncover part of its principles. Motif is a typical structure property that can be well applied to various complex networks. Here, we study the motif changes in C. elegans neural network across development. By counting the occurrence number of all three-node subgraph motif structures in its neural network at different stages of C. elegans development, along with those in corresponding random networks, we determine which of these structures are motifs for C. elegans, finding out the regular changes of motifs during its development. Combined with the potential function of these subgraph motifs and synaptic information, we gain insight into the organizing principle of neural network during development, which may increase our understanding of neuroscience and inspire the construction of artificial neural network.


Assuntos
Algoritmos , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Redes Neurais de Computação
10.
J Hand Surg Am ; 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36038426

RESUMO

PURPOSE: This study aimed to evaluate the radiological and functional results of secondary thumb reconstruction via ectopic banking of bony phalanges from a nonreplantable amputated thumb. METHODS: Thumb reconstruction was performed using the bony phalanges from a nonreplantable amputated thumb that were ectopically banked in a subcutaneous pocket. A wraparound flap was harvested from the ipsilateral great toe and wrapped around the bone graft. After surgery, the results were assessed in terms of infection, range of motion, bone union of the graft, and signs of osseous resorption of the reconstructed thumb. RESULTS: Fifteen patients underwent secondary thumb reconstruction using this technique between January 2003 and October 2018. Ten patients were followed up for at least 6 months (6 months to 9 years) and were included in this study. All wraparound flap transfers were viable. No bone graft infection was observed. In the 6 cases in whom the interphalangeal joint was not fused, the interphalangeal joint motion ranged from 5° to 60° with an average of 35.0° ± 15.1°. The metacarpophalangeal joint motion ranged from 5° to 66°, with an average range of motion of 48.2° ± 23.6° for the cases in whom the joint was not fused. In 8 of the 10 patients, the time of bone ectopic banking was within 10 days. In these patients, bone union with no osseous atrophy was observed. In 2 patients whose phalanx was banked for more than a month, different degrees of bone resorption of the grafted phalanx were evident after transplantation, although no further treatment was required. CONCLUSIONS: Bony phalanges from a nonreplantable amputated thumb can be ectopically banked and used for secondary reconstruction of the thumb. The duration of banking before thumb reconstruction should be no more than 2 weeks. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

11.
Artigo em Inglês | MEDLINE | ID: mdl-35980318

RESUMO

The development of osteoporosis is often accompanied by autophagy disturbance, which also causes new osteoblast defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) is the main enzyme for N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, and it has been implicated in many bioprocesses. Herein, we demonstrate that METTL14 plays a critical role in autophagy induction and hinders osteoporosis process whose expression is decreased both in human osteoporosis bone tissue and ovariectomy (OVX) mice. In vivo, METTL14+/- knockdown mice exhibit elevated bone loss and impaired autophagy similar to the OVX mice, while overexpression of METTL14 significantly promotes bone formation and inhibits the progression of osteoporosis caused by OVX surgery. In vitro, METTL14 overexpression significantly enhances the osteogenic differentiation ability of BMSCs through regulating the expression of beclin-1 depending on m6A modification and inducing autophagy; the opposite is true with METTL14 silencing. Subsequently, m6A-binding proteins IGF2BP1/2/3 recognize m6A-methylated beclin-1 mRNA and promote its translation via mediating RNA stabilization. Furthermore, METTL14 negatively regulates osteoclast differentiation. Collectively, our study reveals the METTL14/IGF2BPs/beclin-1 signal axis in BMSCs osteogenic differentiation and highlights the critical roles of METTL14-mediated m6A modification in osteoporosis.

12.
Front Physiol ; 13: 978222, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35957985

RESUMO

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer, including both non-small cell lung cancer and small cell lung cancer. Despite the promising results of immunotherapies, ICI-related pneumonitis (ICIP) is a potentially fatal adverse event. Therefore, early detection of patients at risk for developing ICIP before the initiation of immunotherapy is critical for alleviating future complications with early interventions and improving treatment outcomes. In this study, we present the first reported work that explores the potential of deep learning to predict patients who are at risk for developing ICIP. To this end, we collected the pretreatment baseline CT images and clinical information of 24 patients who developed ICIP after immunotherapy and 24 control patients who did not. A multimodal deep learning model was constructed based on 3D CT images and clinical data. To enhance performance, we employed two-stage transfer learning by pre-training the model sequentially on a large natural image dataset and a large CT image dataset, as well as transfer learning. Extensive experiments were conducted to verify the effectiveness of the key components used in our method. Using five-fold cross-validation, our method accurately distinguished ICIP patients from non-ICIP patients, with area under the receiver operating characteristic curve of 0.918 and accuracy of 0.920. This study demonstrates the promising potential of deep learning to identify patients at risk for developing ICIP. The proposed deep learning model enables efficient risk stratification, close monitoring, and prompt management of ICIP, ultimately leading to better treatment outcomes.

13.
J Org Chem ; 87(17): 11681-11692, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35984222

RESUMO

Density functional theory (DFT) calculations have been conducted to study the mechanisms, substituent effects, and the role of bases in Au- and Cu-catalyzed hydroacylation of terminal alkyne with glyoxal derivatives. The two reactions, despite being catalyzed by the same group of transition metals, follow distinctive reaction mechanisms. Through the detailed DFT calculations, insights into the mechanisms are obtained, and the substituent effects and the role of the bases are understood.

14.
J Microbiol Biotechnol ; 32(8): 1064-1071, 2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-35879293

RESUMO

Arabinogalactans have diverse biological properties and can be used as pharmaceutical agents. Most arabinogalactans are composed of ß-(1→3)-galactan, so it is particularly important to identify ß-1,3-galactanases that can selectively degrade them. In this study, a novel exo-ß-1,3-galactanase, named PoGal3, was screened from Penicillium oxalicum sp. 68, and hetero-expressed in P. pastoris GS115 as a soluble protein. PoGal3 belongs to glycoside hydrolase family 43 (GH43) and has a 1,356-bp gene length that encodes 451 amino acids residues. To study the enzymatic properties and substrate selectivity of PoGal3, ß-1,3-galactan (AG-P-I) from larch wood arabinogalactan (LWAG) was prepared and characterized by HPLC and NMR. Using AG-P-I as substrate, purified PoGal3 exhibited an optimal pH of 5.0 and temperature of 40°C. We also discovered that Zn2+ had the strongest promoting effect on enzyme activity, increasing it by 28.6%. Substrate specificity suggests that PoGal3 functions as an exo-ß-1,3-galactanase, with its greatest catalytic activity observed on AG-P-I. Hydrolytic products of AG-P-I are mainly composed of galactose and ß-1,6-galactobiose. In addition, PoGal3 can catalyze hydrolysis of LWAG to produce galacto-oligomers. PoGal3 is the first enzyme identified as an exo-ß-1,3-galactanase that can be used in building glycan blocks of crucial glycoconjugates to assess their biological functions.


Assuntos
Glicosídeo Hidrolases , Penicillium , Clonagem Molecular , Galactanos , Especificidade por Substrato
15.
Artigo em Inglês | MEDLINE | ID: mdl-35877000

RESUMO

Because ß-1,6-galactans are significant components in arabinogalactans from plant cell walls, identifying selective endo-ß-1,6-galactanases is crucial to degrading these polysaccharides and to analyzing and modifying their structures. Here, we cloned and expressed in E. coli a novel endo-ß-1,6-galactanase in the glycosidic hydrolase family 30 (GH30) from Penicillium oxalicum. Our recombinant PoGal30 hydrolase (1464 bp gene) that contains an N-terminal His-tag for purification by nickel affinity chromatography has a specific activity of 3.8 U/mg on the substrate de-arabinosylated gum Arabic (dGA) polysaccharide. The enzyme has 487 residues with a molecular mass of 60 kDa, an isoelectric point of 6, and functional pH and temperature optima of pH 2.5 to pH 5.0 and 40 °C, respectively. While the activity of PoGal30 is activated by Mg2+ (5 or 50 mmol/L), it is completely inhibited by Cu2+ and Fe3+ (50 mmol/L) and partially inhibited by Hg2+, EDTA, and SDS (50 mmol/L). The enzyme demonstrates high specificity towards ß-1,6-galactosidic linkages in dGA, but is inactive against aryl-glycosides and galactobioses with different linkages. Using PoGal30 is, therefore, an effective approach to analyzing the fine structure of polysaccharides and preparing bioactive oligosaccharides.

16.
IEEE Trans Cybern ; PP2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35877802

RESUMO

With the rapid development of services computing in the past decade, Quality-of-Service (QoS)-aware selection of Web services has become a hot yet thorny issue. Conducting warming-up tests on a large set of candidate services for QoS evaluation is time consuming and expensive, making it vital to implement accurate QoS-estimators. Existing QoS-estimators barely consider the temporal patterns hidden in QoS data. However, such data are naturally time dependent. For addressing this critical issue, this study presents a Kalman-filter-incorporated latent factor analysis (KLFA)-based QoS-estimator for accurate representation to temporally dynamic QoS data. Its main idea is to make the user latent features (LFs) time dependent, while the service ones time consistent. A novel iterative training scheme is designed, where the user LFs are learned through a Kalman filter for precisely modeling the temporal patterns, and the service ones are alternatively trained via an alternating least squares algorithm for precisely representing the historical QoS data. Empirical studies on large-scale and real Web service QoS datasets demonstrate that the proposed KLFA model significantly outperforms state-of-the-art QoS-estimators in estimation accuracy for dynamic QoS data.

17.
Adv Sci (Weinh) ; : e2105938, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35882624

RESUMO

Autophagy is a highly conserved process that is vital for tumor progression and treatment response. Although autophagy is proposed to maintain the stemness phenotype in adult diffuse glioma, the molecular basis of the link between autophagy and stemness is poorly understood, which makes it impossible to effectively screen for the population that will benefit from autophagy-targeted treatment. Here, ATG9B as essential for self-renewal capacity and tumor-propagation potential is identified. Notably, ASCL2 transcriptionally regulates the expression of ATG9B to maintain stemness properties. The ASCL2-ATG9B axis is an independent prognostic biomarker and indicator of autophagic activity. Furthermore, the highly effective blood-brain barrier (BBB)-permeable autophagy inhibitor ROC-325, which can significantly inhibit the progression of ASCL2-ATG9B axisHigh gliomas as a single agent is investigated. These data demonstrate that a new ASCL2-ATG9B signaling axis is crucial for maintaining the stemness phenotype and tumor progression, revealing a potential autophagy inhibition strategy for adult diffuse gliomas.

18.
Artigo em Inglês | MEDLINE | ID: mdl-35895649

RESUMO

Recently, deep learning has been successfully applied to unsupervised active learning. However, the current method attempts to learn a nonlinear transformation via an auto-encoder while ignoring the sample relation, leaving huge room to design more effective representation learning mechanisms for unsupervised active learning. In this brief, we propose a novel deep unsupervised active learning model via learnable graphs, named ALLGs. ALLG benefits from learning optimal graph structures to acquire better sample representation and select representative samples. To make the learned graph structure more stable and effective, we take into account k -nearest neighbor graph as a priori and learn a relation propagation graph structure. We also incorporate shortcut connections among different layers, which can alleviate the well-known over-smoothing problem to some extent. To the best of our knowledge, this is the first attempt to leverage graph structure learning for unsupervised active learning. Extensive experiments performed on six datasets demonstrate the efficacy of our method.

19.
Sci Rep ; 12(1): 11242, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35787635

RESUMO

To predict disease outcome in muscle-invasive bladder cancer (MIBC), we constructed a prognostic autophagy-related (PAR) lncRNA signature. Comprehensive bioinformatics analyses were performed using data from TCGA and GTEx databases. Univariate Cox, and least absolute shrinkage and selection operator regression analyses were also performed, based on differentially expressed genes, to identify PAR-related lncRNAs to establish the signature. Furthermore, the Kaplan-Meier OS curve and receiver operating characteristic curve analyses were performed and a nomogram was constructed, all of which together confirmed the strong predictive ability of the constructed signature. Patients with MIBC were then divided into high- and low-risk groups. Gene enrichment and immune infiltration analyses revealed the potential mechanisms in MIBC. We also further evaluated the signature of molecules related to immune checkpoints and the sensitivity toward chemotherapeutic agents and antitumor-targeted drugs to find better treatment prescriptions. We identified a number of PAR-related lncRNA signatures, including HCP5, AC024060.1, NEAT1, AC105942.1, XIST, MAFG-DT, and NR2F1-AS1, which could be valuable prognostic tools to develop more efficient, individualized drug therapies for MIBC patients.


Assuntos
RNA Longo não Codificante , Neoplasias da Bexiga Urinária , Autofagia/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia
20.
Placenta ; 126: 150-159, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35816776

RESUMO

INTRODUCTION: Throughout human pregnancy there is a delicate balance between the maintenance of a proliferative, trophoblast stem cell pool (TSC) and the differentiation from TSC to placental cell sub-lineages like the syncytiotrophoblast (STB). The STB is comprised of multinucleated cells that come into direct contact with maternal blood and provides the first line of defense to protect the fetus from maternal infections. The differentiation of TSC towards STB is primarily driven by human endogenous retroviruses (HERV), specifically Syncytin-1 (ERVW-1) and Syncytin-2 (ERVFRD-1). Beyond cell fusion, there is also evidence to suggest they can regulate cell proliferation and an antiviral response in other cell types. Therefore, we hypothesized that HERV can regulate cell proliferation as well as an antiviral response in TSCs. METHOD: shRNA was used to knockdown ERVW-1 in TSCs and revealed reduction in cell proliferation, differentiation, and cell fusion. RT-qPCR and flow cytometry was used to measure other HERV and the presence of Type I and Type II interferon receptors. RESULTS: ERVW-1 knockdown (KD) TSCs had a significantly longer cell doubling time and reduced expression of the proliferation marker Ki67. ERVW-1 KD cells also demonstrated a marked deficiency in the ability to differentiate. Interestingly, ERVFRD-1 was upregulated in both ERVW-1 KD TSC and STB cells compared to controls. Finally, we found that the Type I interferon receptors, IFNAR1 and IFNAR2 were significantly increased in ERVW-1 KD STB cells. DISCUSSION: These findings uncover critical HERV functions in the trophoblasts and a novel role for ERVW-1 during early human placental development.


Assuntos
Retrovirus Endógenos , Trofoblastos , Antivirais , Proliferação de Células , Retrovirus Endógenos/genética , Feminino , Produtos do Gene env , Humanos , Placenta/metabolismo , Gravidez , Proteínas da Gravidez , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Trofoblastos/metabolismo
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