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1.
Acta Pharmacol Sin ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32203085

RESUMO

Ginsenoside Rg1 is one of the most active ingredients in ginseng, which has been reported to protect dopaminergic neurons and improve behavioral defects in MPTP model, 6-OHDA model and rotenone model. However, it is unclear whether Rg1 exerted neuroprotection in LPS-induced sub-acute PD model. In this study, we investigated the neuroprotective effect of Rg1 in the sub-acute PD mouse model and explored the related mechanisms. Rg1 (10, 20, 40 mg·kg-1·d-1) was orally administered to mice for 18 days. A sub-acute PD model was established in the mice through LPS microinjection into the substantia nigra (SN) from D8 to D13. We found that Rg1 administration dose-dependently inhibited LPS-induced damage of dopaminergic neurons and activation of glial cells in the substantia nigra pars compacta (SNpc). The neuroprotective effects of Rg1 were associated with the reduction of pro-inflammatory cytokines and the improvement of anti-inflammatory cytokines and neurotrophin in the midbrain. Rg1 shifted the polarization of microglia towards the M2 phenotype from M1, evidenced by decreased M1 markers (inducible NO synthase, CD16, etc.) and increased M2 markers (arginase 1 (Arg1), CD206, etc) in the midbrain. Furthermore, Rg1 administration markedly inhibited nuclear translocation of NF-κB in midbrain microglia. In conclusion, Rg1 protects PD mice induced by continuous LPS injection by inhibiting the nuclear entry of NF-κB and regulating the polarization balance of microglia, shedding new light on a disease-modifying therapy of PD.

2.
Viruses ; 12(3)2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32182849

RESUMO

Pigs are considered a "mixing vessel" that can produce new influenza strains through genetic reassortments, which pose a threat to public health and cause economic losses worldwide. The timely surveillance of the epidemiology of the swine influenza virus is of importance for prophylactic action. In this study, 15 H1N1, one H1N2, and four H3N2 strains were isolated from a total of 4080 nasal swabs which were collected from 20 pig farms in three provinces in China between 2016 and 2019. All the isolates were clustered into four genotypes. A new genotype represented by the H1N2 strain was found, whose fragments came from the triple reassortant H1N2 lineage, classical swine influenza virus (cs-H1N1) lineage, and 2009 H1N1 pandemic virus lineage. A/Sw/HB/HG394/2018(H1N1), which was clustered into the cs-H1N1 lineage, showed a close relationship with the 1918 pandemic virus. Mutations determining the host range specificity were found in the hemagglutinin of all isolates, which indicated that all the isolates had the potential for interspecies transmission. To examine pathogenicity, eight isolates were inoculated into 6-week-old female BALB/c mice. The isolates replicated differently, producing different viral loadings in the mice; A/Swine/HB/HG394/2018(H1N1) replicated the most efficiently. This suggested that the cs-H1N1 reappeared, and more attention should be given to the new pandemic to pigs. These results indicated that new reassortments between the different strains occurred, which may increase potential risks to human health. Continuing surveillance is imperative to monitor swine influenza A virus evolution.

3.
Environ Int ; 138: 105593, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32120062

RESUMO

The ribosomal DNA (rDNA) can act as a sensor and responder of cancer-associated stress. Here we investigated rDNA copy number in gastric cancers and its association with existing biomarkers and metals exposure. This study was performed on paired tumor and adjacent normal tissues obtained from 65 gastric cancer patients who underwent gastrectomy. Immunohistochemistry was used to assess HER-2, E-cadherin, EGFR, CK (pan), CK20, CK7, TopoⅡ, CAM5.2, P53, and Ki-67 expression. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect the concentrations of 17 metals in gastric tissues. rDNA copy number was detected by qPCR in genomic DNA isolated from tissue samples. Associations between the expression of existing markers, metal concentrations, and rDNA copy number were evaluated. Within patients with gastric cancer, the copy number of the 45S rDNA components (18S, 5.8S, 28S) and the 5S rDNA in tumor tissues were significantly higher than those in adjacent normal tissues, whereas mitochondrial DNA (mtDNA) copy number was significantly lower in tumor tissues than that in adjacent normal tissues. Further analysis revealed that the increase in 18S, 5.8S, and 28S rDNA copy number in tumor tissues was diminished in the context of EGFR and P53 loss. Moreover, analysis of metals revealed particularly high concentrations of As, Cd, Cr, Cu and Fe in the gastric tissues of these patients. Intriguingly, rDNA copy number variation across individuals was correlated with the concentrations of some metals. The rDNA was amplified in tumor tissues of gastric cancer patients, and its amplification may be associated with metals exposure. The expression of EGFR and P53 may influence rDNA copy number, with diminished amplification of the rDNA in cancers that were negative for these biomarkers. Our observation further our understanding of rDNA copy number in gastric cancer and its potential as a simple and useful marker in gastric cancer monitoring.

4.
Environ Int ; 138: 105641, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32203804

RESUMO

Disinfection is an essential process of drinking water treatment to eliminate harmful pathogens, but it generates potentially toxic disinfection byproducts (DBPs). Ferrate (FeO42-, Fe(VI)) was used to pre-oxidize natural organic matter (NOM, the precursor of DBPs) in source water to control DBP formation in subsequent chlorine or chloramine disinfection. Currently, it is unclear how Fe(VI) changes the structure of NOM, and no information details the effect of Fe(VI) pretreatment on the aromatic DBPs or the speciation of overall DBPs generated in subsequent disinfection of drinking water. In the present paper, Fe(VI) was applied to pretreat simulated source water samples at a Fe(VI) to dissolved organic carbon mole ratio of 1:1 at pH 8.0. 13C nuclear magnetic resonance spectroscopy was newly employed to characterize NOM in simulated source waters with and without Fe(VI) treatment, and it was demonstrated that Fe(VI) converted unsaturated aromatic C functional groups in NOM to saturated aliphatic ones. High-resolution mass spectrometry (HRMS) and high performance liquid chromatography/triple quadrupole MS were applied to analyze the DBPs generated in chlorination and chloramination of the source waters with and without Fe(VI) pretreatment. It was confirmed that Fe(VI) pretreatment followed by chlorination (or chloramination), generated DBPs containing less unsaturated, halogenated, and aromatic moieties than chlorination (or chloramination) without pretreatment by Fe(VI). Finally, the cytotoxicity of disinfected drinking water samples were assessed with the human epithelial colorectal adenocarcinoma Caco-2 cell line (a model of the intestinal barrier for ingested toxicants), and the results show that Fe(VI) pretreatment detoxified the chlorinated and chloraminated drinking waters.

5.
Anal Chim Acta ; 1101: 184-192, 2020 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-32029110

RESUMO

An automatic online solid-phase dehydrate extraction (SPDE)-ultra-high performance supercritical fluid chromatography (UHPSFC)-MS/MS system was developed in this study, in which the automatic SPDE procedure was coupled with UHPSFC to allow UHPSFC to analyze aqueous samples directly. Moreover, a pre-column dilution strategy was employed, which focused the analytes in strong desorption solvent on the column head and helped to obtain narrow and symmetric peaks. The online SPDE-UHPSFC-MS/MS system was firstly applied to the screening of 45 prohibited substances in human urine for doping control, during which all the mechanisms and features of the online system were fully studied. The majority (91%) of the target compounds achieved weak matrix effects (80-120%), indicating that the online method was accurate and reliable thanks to the SPDE procedure and efficient UHPSFC separation. Owing to the reduction of the matrix effects, large volume injection and the pre-column dilution, the online system could achieve high sensitivity with the LODs ranging from 0.0380 ng L-1 to 1.24 µg L-1. Under the optimized conditions, the extraction recoveries of 66% target analytes were more than 50%. All the target compounds showed good linearity with linear correlation coefficients higher than 0.9928. The accuracy values of all the spiked prohibited substances were within 80.8-119.7%, while the RSDs% for the intra-/inter-day precision were within 10.8% and 15.4%. Compared with the dilute-and-shoot-ultra-high performance liquid chromatography-MS/MS method, in which the urine samples were simply diluted before analyzing, this online method was superior in sensitivity and reducing matrix effects, which demonstrated its utility in doping control. Compared with the previously reported online SPE-SFC system, the online SPDE-UHPSFC-MS/MS system showed advantages in automation, efficiency, sensitivity and chromatographic performance. In summary, the online SPDE-UHPSFC-MS/MS system is capable of analyzing complex aqueous samples.

6.
Arch Suicide Res ; : 1-17, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32013796

RESUMO

The integrated motivational-volitional model of suicidal behavior (IMV; O'Connor & Kirtley, 2018) integrates some key factors of suicidal behavior (e.g., defeat and entrapment) to explain the development of suicidal ideation and suicidal attempts. This study aimed to empirically test this model in a sample of Chinese adolescents. A number of 1,239 Chinese adolescents (679 girls; Mage = 14.07, SD = 1.54) completed self-report questionnaires. Results showed that defeat was associated with entrapment, which, in turn, was related to suicidal ideation and suicidal attempts. In addition, the relationship between entrapment and suicidal ideation was significant at high levels of thwarted belongingness and perceived burdensomeness, and low levels of resilience. These findings support the application of the IMV model in Chinese adolescents, and might help mental health organizations and educational agencies formulate effective suicidal prevention programs geared toward Chinese adolescents.

7.
Colloids Surf B Biointerfaces ; 189: 110875, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32087532

RESUMO

Due to the overuse of antibiotics, vancomycin resistant enterococci (VRE) has caused serious infections and become more and more difficult to deal with. Herein, we reported a facile one-pot strategy to synthesize copper sulfide nanoparticles using vancomycin (Van) as reductant and capping agent (CuS@Van). The as-prepared CuS@Van nanocomposites presented excellent uniformity in particle size and strong near infrared (NIR) absorbance. Fourier Transform infrared spectroscopy (FTIR) and Energy dispersive spectrometry (EDS) analysis confirmed the successful modification of Van molecules on the surface of CuS@Van nanoparticles. Bacterial TEM images verified the specific binding affinity between CuS@Van and VRE pathogen. CuS@Van also exhibited effective photokilling capability based on a combination of photothermal therapy (PTT) and photodynamic therapy (PDT). Fluorescent bacterial viability staining and bacterial growth curves monitoring were performed to explore the photokilling ablation of CuS@Van against VRE pathogens. The in vitro results indicated that CuS@Van nanocomposites had no antibacterial activity in the dark but displayed satisfying bactericidal effect against VRE pathogens upon the NIR irradiation. Mouse infection assays were also implemented to evaluate in vivo antibacterial photokilling effectiveness. CuS@Van with NIR irradiation showed the highest antibacterial capability and fastest infection regression compared with the control groups. Considering the low cost, easy preparation, good biocompatibility and excellent photokilling capability, CuS@Van nanocomposites will shed bright light on the photokilling ablation of vancomycin-resistant pathogenic bacteria.

8.
Korean J Radiol ; 21(3): 365-368, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32056397

RESUMO

Since the 2019 novel coronavirus (2019-nCoV or officially named by the World Health Organization as COVID-19) outbreak in Wuhan, Hubei Province, China in 2019, there have been a few reports of its imaging findings. Here, we report two confirmed cases of 2019-nCoV pneumonia with chest computed tomography findings of multiple regions of patchy consolidation and ground-glass opacities in both lungs. These findings were characteristically located along the bronchial bundle or subpleural lungs.


Assuntos
Brônquios/diagnóstico por imagem , Infecções por Coronavirus/diagnóstico por imagem , Surtos de Doenças , Pulmão/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , China , Infecções por Coronavirus/patologia , Febre/etiologia , Humanos , Masculino , Pneumonia Viral/patologia , Radiografia Torácica , Organização Mundial da Saúde
9.
J Mol Biol ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32087196

RESUMO

Cells have evolved molecular chaperones that modulate phase separation and misfolding of amyloidogenic proteins to prevent neurodegenerative diseases. Protein disulfide isomerase (PDI), mainly located at the endoplasmic reticulum and also present in the cytosol, acts as both an enzyme and a molecular chaperone. PDI is observed to be S-nitrosylated in the brain of Alzheimer's disease patients, but the mechanism has remained elusive. We herein report that both wild-type PDI and its quadruple cysteine mutant only having chaperone activity, significantly inhibit pathological phosphorylation and abnormal aggregation of Tau in cells, and significantly decrease the mitochondrial damage and Tau cytotoxicity resulting from Tau aberrant aggregation, highlighting the chaperone property of PDI. More importantly, we show that wild-type PDI is selectively recruited by liquid droplets of Tau, which significantly inhibits phase separation and stress granule formation of Tau, whereas S-nitrosylation of PDI abrogates the recruitment and inhibition. These findings demonstrate how phase separation of Tau is physiologically regulated by PDI and how S-nitrosylation of PDI, a perturbation in this regulation, leads to disease.

10.
Sci Adv ; 6(1): eaax5819, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911943

RESUMO

Autophagy is an evolutionarily conserved catabolic process, which plays a vital role in removing misfolded proteins and clearing damaged organelles to maintain internal environment homeostasis. Here, we uncovered the checkpoint kinase 2 (CHK2)-FOXK (FOXK1 and FOXK2) axis playing an important role in DNA damage-mediated autophagy at the transcriptional regulation layer. Mechanistically, following DNA damage, CHK2 phosphorylates FOXK and creates a 14-3-3γ binding site, which, in turn, traps FOXK proteins in the cytoplasm. Because FOXK functions as the transcription suppressor of ATGs, DNA damage-mediated FOXKs' cytoplasmic trapping induces autophagy. In addition, we found that a cancer-derived FOXK mutation induces FOXK hyperphosphorylation and enhances autophagy, resulting in chemoresistance. Cotreatment with cisplatin and chloroquine overcomes the chemoresistance caused by FOXK mutation. Overall, our study highlights a mechanism whereby DNA damage triggers autophagy by increasing autophagy genes via CHK2-FOXK-mediated transcriptional control, and misregulation of this pathway contributes to chemoresistance.

11.
Environ Sci Technol ; 54(6): 3386-3394, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-31961660

RESUMO

Although the fate of nanoplastics (<100 nm) in freshwater systems is increasingly well studied, much less is known about its potential threats to cyanobacterial blooms, the ultimate phenomenon of eutrophication occurrence worldwide. Previous studies have evaluated the consequences of nanoplastics increasing the membrane permeability of microbes, however, there is no direct evidence for interactions between nanoplastics and microcystin; intracellular hepatotoxins are produced by some genera of cyanobacteria. Here, we show that the amino-modified polystyrene nanoplastics (PS-NH2) promote microcystin synthesis and release from Microcystis aeruginosa, a dominant species causing cyanobacterial blooms, even without the change of coloration. We demonstrate that PS-NH2 inhibits photosystem II efficiency, reduces organic substance synthesis, and induces oxidative stress, enhancing the synthesis of microcystin. Furthermore, PS-NH2 promotes the extracellular release of microcystin from M. aeruginosa via transporter protein upregulation and impaired cell membrane integrity. Our findings propose that the presence of nanoplastics in freshwater ecosystems might enhance the threat of eutrophication to aquatic ecology and human health.

12.
ACS Synth Biol ; 9(2): 457-460, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31999442

RESUMO

Burkholderiales are an emerging source of bioactive secondary metabolites and have the potential to be a robust chassis for metabolites from Gram-negative bacteria. However, only a few constitutive promoters can be utilized in Burkholderiales. Herein, we described the screening of strong constitutive promoters from Burkholderiales strain DSM 7029, and 37 promoters identified from transcriptome sequencing were cloned and characterized using a firefly luciferase reporter and were further verified by qPCR analysis. These promoters were then used to drive a complex 56-kb epothilone BGC from myxobacterium and a 23-kb rhizomide BGC from Paraburkholderia rhizoxinica, and the successful production of epothilone and rhizomide was observed in DSM 7029, with improved yields compared to the production achieved by previously used promoters. Additionally, these promoters are also functional in other Burkholderiales species. Thus, these promoters are highly useful for optimizing yields of important metabolites in Burkholderiales and for mining cryptic biosynthetic pathways in DSM 7029.

13.
J Hazard Mater ; 384: 121503, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31708286

RESUMO

Organochlorines are critical soil contaminants and the use of biochar has recently shown potential to improve soil remediation. However, little is known about biochar-microbe interactions nor the impact on environmental processes such as the immobilization and biodegradation of organochlorine compounds. In this study, we performed microcosm experiments to elucidate how biochar affected the biodegradation and sequestration of pentachlorophenol (PCP). Our results showed that the amendment of biochar markedly inhibited PCP biodegradation due to a strong sorption affinity for PCP under both aerobic and anaerobic conditions. Notably, the inhibitory effect was relatively weaker under anaerobic conditions than under aerobic conditions. The addition of biochar can dramatically shift the bacterial community diversity in the PCP-spiked soils. Under aerobic conditions, biochar significantly stimulated the growth of PCP-degrading bacteria Bacillus and Sphingomonas, but reduced the opportunities for microbes to contact with PCP directly. Under anaerobic conditions, the non-strict organohalide-respiring bacteria Desulfovibrio, Anaeromyxobacter, Geobacter and Desulfomonile were the main drivers of PCP transformation. Our results imply that the use of biochar as a soil remediation strategy for organochlorine compounds should be cautious.

14.
Indoor Air ; 30(2): 213-234, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31709614

RESUMO

Low-cost airborne particle sensors are gaining attention for monitoring human exposure to indoor particulate matter. This study aimed to establish the concentrations at which these commercially available sensors can be expected to report accurate concentrations. We exposed five types of commercial integrated devices and three types of "bare" low-cost particle sensors to a range of concentrations generated by three different sources. We propose definitions of upper and lower bounds of functional range based on the relationship between a given sensor's output and that of a reference instrument during a laboratory experiment. Experiments show that the lower bound can range from approximately 3 to 15 µg/m3 . At greater concentrations, sensor output deviates from linearity at approximately 300-3000 µg/m3 . We also conducted a simulation campaign to analyze the effect of this limitation on functional range on the accuracy of exposure readings given by these devices. We estimate that the upper bound results in minimal inaccuracy in exposure quantification, and the lower bound can result in as much as a 50% error in approximately 10% of US homes.

15.
Curr Microbiol ; 77(1): 123-128, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31664502

RESUMO

Phage PA-YS35 is a novel lytic Pseudomonas aeruginosa phage belonging to the Myoviridae family and was isolated from the sewage of the First Hospital of Jilin University. The biological properties testing indicated that phage PA-YS35 is stable between - 20 and 60 °C and pH 4-9. The one-step growth curve shows that the latent period of PA-YS35 was 9 min, and the burst period was about 21 min by the size of approximately 380 progeny phages per host cell. The genome of phage PA-YS35 is linear double-stranded DNA with a size of 93,296 bp and a GC content of 49.35%. The results from RAST gene annotation analysis showed that the PA-YS35 genome contains 172 open reading frames (ORFs); the function of 41 ORFs can be predicted, whereas the product of remaining 131 ORFs are hypothetical proteins. According to phylogenetic tree of RNA ligase encoding sequence, phage PA-YS35 has a close evolutionary relationship with Pseudomonas phage PAK P1 because both of them are located on the same branch. The study of phage PA-YS35 genome will provide useful information for further research on the interaction between phages and their hosts.

16.
Plant Cell Environ ; 43(3): 732-744, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31724184

RESUMO

Silicon (Si) accumulation in shoots differs greatly with plant species, but the molecular mechanisms for this interspecific difference are unknown. Here, we isolated homologous genes of rice Si influx (SlLsi1) and efflux (SlLsi2) transporter genes in tomato (Solanum lycopersicum L.) and functionally characterized these genes. SlLsi1 showed transport activity for Si when expressed in both rice lsi1 mutant and Xenopus laevis oocytes. SlLsi1 was constitutively expressed in the roots. Immunostaining showed that SlLsi1 was localized at the plasma membrane of both root tip and basal region without polarity. Furthermore, overexpression of SlLsi1 in tomato increased Si concentration in the roots and root cell sap but did not alter the Si concentration in the shoots. By contrast, two Lsi2-like proteins did not show efflux transport activity for Si in Xenopus oocytes. However, when functional CsLsi2 from cucumber was expressed in tomato, the Si uptake was significantly increased, resulting in higher Si accumulation in the leaves and enhanced tolerance of the leaves to water deficit and high temperature. Our results suggest that the low Si accumulation in tomato is attributed to the lack of functional Si efflux transporter Lsi2 required for active Si uptake although SlLsi1 is functional.

17.
Cell Tissue Res ; 379(3): 537-548, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31776823

RESUMO

Abnormal activation of Wnt signaling has been demonstrated in the wound healing process and the pathogenesis of fibrotic disorders, with Wnt4 specifically identified as having a key role in the pathogenesis of renal, pulmonary and liver fibrosis. Wnt4 also was found to be upregulated by transforming growth factor-ß1 (TGF-ß1) in fetal and postnatal murine fibroblasts and bone marrow mesenchymal cells, suggesting an underlying cooperation between Wnt4 and TGF-ß1 in fibrosis. However, the specific roles of Wnt4 in TGF-ß1-induced skin myofibroblast transition and hypertrophic scar formation remain unclear. In the present study, we first observed reduced Wnt4 expression in hypertrophic scar tissue compared with that in normal skin tissue. Following upregulation by TGF-ß1, Wnt4 inhibited the TGF-ß1-induced transdifferentiation of fibroblasts into myofibroblasts. Using fibroblast-populated collagen lattice contraction assays, we showed that the increased contractility induced by TGF-ß1 was significantly blocked by exogenous Wnt4 and the α-smooth muscle actin (α-SMA) expression was decreased in fibroblasts in the collagen lattices. In addition, knockdown of Wnt4 resulted in further increases in α-SMA and collagen I expressions. Further investigation showed that Wnt4 could inhibit the autocrine effect of TGF-ß1 as well as block the phosphorylation of Smad3 and ERK but not of AKT or JNK. Lastly, using hypertrophic scar-derived fibroblasts, we showed that the elevated α-SMA and collagen I levels were markedly reduced after treatment with Wnt4. Taken together, our results suggest that Wnt4 negatively regulates TGF-ß1-induced fibroblast activation, which may represent a novel therapeutic strategy for the treatment and prevention of hypertrophic scars.

18.
Mol Genet Genomic Med ; 8(1): e1023, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31774634

RESUMO

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

19.
Nucleic Acids Res ; 48(D1): D40-D44, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31428785

RESUMO

Epigenetic alterations, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and nucleosome positioning (NP), in cell-free DNA (cfDNA) have been widely observed in human diseases, and many available cfDNA-based epigenome-wide profiles exhibit high sensitivity and specificity in disease detection and classification. However, due to the lack of efficient collection, standardized quality control, and analysis procedures, efficiently integrating and reusing these data remain considerable challenges. Here, we introduce CFEA (http://www.bio-data.cn/CFEA), a cell-free epigenome database dedicated to three types of widely adopted epigenetic modifications (5mC, 5hmC and NP) involved in 27 human diseases. We developed bioinformatic pipelines for quality control and standard data processing and an easy-to-use web interface to facilitate the query, visualization and download of these cell-free epigenome data. We also manually curated related biological and clinical information for each profile, allowing users to better browse and compare cfDNA epigenomes at a specific stage (such as early- or metastasis-stage) of cancer development. CFEA provides a comprehensive and timely resource to the scientific community and supports the development of liquid biopsy-based biomarkers for various human diseases.

20.
Hum Mutat ; 41(1): 182-195, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31471994

RESUMO

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

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