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1.
Clin Cardiol ; 44(6): 833-838, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33955019

RESUMO

BACKGROUND: Premature ventricular contractions (PVCs) may increase during pregnancy, however, few studies have evaluated the relationship between PVCs and the pregnant outcomes. HYPOTHESIS: PVCs may increase the adverse fetal/neonatal outcomes in pregnant women. METHODS: Six thousand one hundred and forty-eight pregnant women were prospectively enrolled in our center between 2017 and 2019 in the study. The average PVC burden was determined by calculating the number of PVCs in total beats. Those who had a PVC burden >0.5% were divided into two groups based on the presence or absence of adverse fetal or neonatal events. The adverse outcomes were compared between the groups to assess the impact of PVCs on pregnancy. RESULTS: A total of 103 (1.68%) women with a PVC burden >0.5% were recorded. Among them, 17 adverse events (12 cases) were documented, which was significantly higher than that among women without PVCs (11.65% vs. 2.93%, p < .01). The median PVC burden among pregnant women with PVCs was 2.84% (1.02%-6.1%). Furthermore, compared with that of the women without adverse events, the median PVC burden of women with adverse fetal or neonatal outcomes was significantly higher (9.02% vs. 2.30%, p < .01). Multivariate logistic regression analysis demonstrated that not the LVEF, heart rate and bigeminy, but only the PVC burden was associated with adverse fetal or neonatal outcomes among pregnant women with PVCs (OR: 1.34, 95% CI [1.11-1.61], p < .01). CONCLUSIONS: Frequent PVCs have adverse effects on pregnancy, and the PVC burden might be an important factor associated with adverse fetal and neonatal outcomes among pregnant women with PVCs.

2.
FASEB J ; 35(6): e21675, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34038004

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-É£ (PPARÉ£) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.

3.
Int J Biol Sci ; 17(5): 1178-1190, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33867838

RESUMO

Growing evidence indicates N6-methyladenosine (m6A) has biological function in oncogenesis. METTL3, the catalytic component, is the most important part of methyltransferase complex and plays a crucial role in cancers. However, the biological function of circRNAs derived from METTL3 in breast cancer and the underlying molecular mechanism remains unclear. Herein, we report circMETTL3, which has not been explored in breast cancer, and it is markedly upregulated in breast cancer. Moreover, we uncovered that circMETTL3 could facilitate cell proliferation, migration and invasion in breast cancer. Mechanism investigation showed that circMETTL3 might act as a competing endogenous RNA (ceRNA) of miR-31-5p and upregulate its target cyclin-dependent kinases (CDK1). Moreover, m6A modification of circMETTL3 might affect its expression. Taken together, our results elucidate that circMETTL3 promotes breast cancer progression through circMETTL3/miR-31-5p/CDK1 axis. Moreover, METTL3, the host gene of circMETTL3, may regulate circMETTL3 expression in an m6A-dependent manner, while circMETTL3 has no effect on METTL3 expression, providing a new relationship between the circRNA and the corresponding host gene. Thus, it may serve as a new therapeutic target for breast cancer.

4.
J Immunother Cancer ; 9(4)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33795388

RESUMO

BACKGROUND: Despite great advances in the treatment of breast cancer, innovative approaches are still needed to reduce metastasis. As a minimally invasive local therapy (not standard therapy for breast cancer), microwave ablation (MWA) has been attempted to treat breast cancer, but the local effect and immune response induced by MWA have seldom been reported. METHODS: The clinical study was performed to determine the complete ablation rate of MWA for early-stage breast cancer. Secondary endpoints included safety and antitumor immune response. 35 subjects from this clinical study were enrolled in the current report, and the local effect was determined by pathological examinations or follow-up. To investigate MWA-induced immune response, patients treated with surgery (n=13) were enrolled as control, and blood samples were collected before and after MWA or surgery. The immune cell populations, serum cytokines, secretory immune checkpoint molecules, and T-cell receptor sequencing were analyzed. RESULTS: Of 35 enrolled patients, 32 (91.4%) showed complete ablation. Compared with surgery, MWA induced significantly increased levels of inducible co-stimulator (ICOS)+ activated CD4+ T cells and serum interferon gamma, indicating a shift in the Th1/Th2 balance toward Th1. The activated ICOS pathway was involved in the MWA-induced adaptive immune response. T-cell receptor sequencing revealed MWA of primary tumor activated T lymphocytes expansion and recognized some cancer-specific antigens. Moreover, CD4+ effector memory T-cell response was induced by MWA, and the immune response still existed after surgical resection of the ablated tumor. CONCLUSIONS: MWA may not only be a promising local therapy but also a trigger of antitumor immunity for breast cancer, opening new avenues for the treatment of breast cancer. Combinatorial strategy using additional agents which boost MWA-induced immune response could be considered as potential treatment for clinical study for early breast cancer therapy.

5.
Appl Microbiol Biotechnol ; 105(8): 3101-3113, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33818672

RESUMO

Regulating morphology engineering and fermentation of Aspergillus oryzae makes it possible to increase the titer of L-malate. However, the existing L-malate-producing strain has limited L-malate production capacity and the fermentation process is insufficiently mature, which cannot meet the needs of industrial L-malate production. To further increase the L-malate production capacity of A. oryzae, we screened out a mutant strain (FMME-S-38) that produced 79.8 g/L L-malate in 250-mL shake flasks, using a newly developed screening system based on colony morphology on the plate. We further compared the extracellular nitrogen (N1) and intracellular nitrogen (N2) contents of the control and mutant strain (FMME-S-38) to determine the relationship between the curve of nitrogen content (N1 and N2) and the L-malate titer. This correlation was then used to optimize the conditions for developing a novel nitrogen supply strategy (initial tryptone concentration of 6.5 g/L and feeding with 3 g/L tryptone at 24 h). Fermentation in a 7.5-L fermentor under the optimized conditions further increased the titer and productivity of L-malate to 143.3 g/L and 1.19 g/L/h, respectively, corresponding to 164.9 g/L and 1.14 g/L/h in a 30-L fermentor. This nitrogen regulation-based strategy cannot only enhance industrial-scale L-malate production but also has generalizability and the potential to increase the production of similar metabolites.Key Points• Construction of a new screening system based on colony morphology on the plate.• A novel nitrogen regulation strategy used to regulate the production of L-malate.• A nitrogen supply strategy used to maximize the production of L-malate.


Assuntos
Aspergillus oryzae , Aspergillus oryzae/genética , Fermentação , Malatos , Nitrogênio
6.
Cancers (Basel) ; 13(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807786

RESUMO

Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvß3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvß3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvß3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvß3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvß3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.

7.
Int J Oncol ; 58(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846777

RESUMO

Septin 6 (SEPT6) is a member of the GTP­binding protein family that is highly conserved in eukaryotes and regulates various biological functions, including filament dynamics, cytokinesis and cell migration. However, the functional importance of SEPT6 in hepatocellular carcinoma (HCC) is not completely understood. The present study aimed to investigate the expression levels and roles of SEPT6 in HCC, as well as the underlying mechanisms. The reverse transcription quantitative PCR, western blotting and immunohistochemistry staining results demonstrated that SEPT6 expression was significantly elevated in HCC tissues compared with corresponding adjacent non­tumor tissues, which indicated that SEPT6 expression may serve as a marker of poor prognosis for HCC. By performing plasmid transfection and G418 treatment, stable SEPT6­knockdown and SEPT6­overexpression cell lines were established. The Cell Counting Kit­8, flow cytometry and Transwell assay results demonstrated that SEPT6 overexpression significantly increased HCC cell proliferation, cell cycle transition, migration and invasion compared with the Vector group, whereas SEPT6 knockdown displayed significant suppressive effects on HCC cell lines in vitro compared with the control group. Mechanistically, SEPT6 might facilitate F­actin formation, which induced large tumor suppressor kinase 1 dephosphorylation, inhibited Hippo signaling, upregulated yes­associated protein (YAP) expression and nuclear translocation, and upregulated cyclin D1 and matrix metallopeptidase 2 (MMP2) expression. Furthermore, YAP overexpression significantly reversed SEPT6 knockdown­induced inhibitory effects on HCC, whereas YAP knockdown significantly inhibited the oncogenic effect of SEPT6 overexpression on HCC. Collectively, the present study demonstrated that SEPT6 may promote HCC progression by enhancing YAP activation, suggesting that targeting SEPT6 may serve as a novel therapeutic strategy for HCC.

8.
Microb Pathog ; 156: 104915, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33930416

RESUMO

Staphylococcus aureus is one of the leading hospital-associated and community-associated pathogens, which has caused a global public health concern. The emergence of methicillin-resistant S. aureus (MRSA) along with the widespread use of different classes of antibiotics has become a significant therapeutic challenge. Antibiotic resistance is a disturbing problem that poses a threat to humans. Treatment options for S. aureus resistant to ß-lactam antibiotics include glycopeptide antibiotic, cyclic lipopeptide antibiotic, cephalosporins and oxazolidinone antibiotic. The most representative types of these antibiotics are vancomycin, daptomycin, ceftaroline and linezolid. The frequent use of the first-line drug vancomycin for MRSA treatment has increased the number of resistant strains, namely vancomycin intermediate resistant S. aureus (VISA) and vancomycin resistant S. aureus (VRSA). A systematic literature review of relevant published studies in PubMed before 2020 was conducted. In recent years, there have been some reports on the relevant resistant mechanisms of vancomycin, daptomycin, ceftaroline and linezolid. In this review, we have summarized the antibiotic molecular modes of action and different gene mutants at the whole-genome level, which will aid in further development on new drugs for effective MRSA treatment based on describing different resistance mechanisms of classic antibiotics.

9.
PLoS Pathog ; 17(3): e1009439, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33711082

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the global pandemic of COVID-19. SARS-CoV-2 is classified as a biosafety level-3 (BSL-3) agent, impeding the basic research into its biology and the development of effective antivirals. Here, we developed a biosafety level-2 (BSL-2) cell culture system for production of transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP). This trVLP expresses a reporter gene (GFP) replacing viral nucleocapsid gene (N), which is required for viral genome packaging and virion assembly (SARS-CoV-2 GFP/ΔN trVLP). The complete viral life cycle can be achieved and exclusively confined in the cells ectopically expressing SARS-CoV or SARS-CoV-2 N proteins, but not MERS-CoV N. Genetic recombination of N supplied in trans into viral genome was not detected, as evidenced by sequence analysis after one-month serial passages in the N-expressing cells. Moreover, intein-mediated protein trans-splicing approach was utilized to split the viral N gene into two independent vectors, and the ligated viral N protein could function in trans to recapitulate entire viral life cycle, further securing the biosafety of this cell culture model. Based on this BSL-2 SARS-CoV-2 cell culture model, we developed a 96-well format high throughput screening for antivirals discovery. We identified salinomycin, tubeimoside I, monensin sodium, lycorine chloride and nigericin sodium as potent antivirals against SARS-CoV-2 infection. Collectively, we developed a convenient and efficient SARS-CoV-2 reverse genetics tool to dissect the virus life cycle under a BSL-2 condition. This powerful tool should accelerate our understanding of SARS-CoV-2 biology and its antiviral development.


Assuntos
/virologia , Técnicas de Cultura de Células/métodos , /fisiologia , Antivirais/farmacologia , Contenção de Riscos Biológicos , Genoma Viral/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , /genética , Replicação Viral/efeitos dos fármacos
10.
J Org Chem ; 86(7): 5110-5119, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33724032

RESUMO

The 1,5-benzodiazepines are important skeletons frequently contained in medicinal chemistry. Herein, we described an unexpected tandem cyclization/transfer hydrogenation reaction for obtaining chiral 2,3-disubstituted 1,5-benzodiazepines. The enolizable aryl aldehydes were chosen as substrates to react with symmetric and unsymmetric o-phenylenediamines. The unforeseen tandem reaction occurred among many possible latent side reactions under chiral phosphoric acid catalysis and affords the corresponding products in moderate yields and regioselectivities, good diastereoselectivities, and enantiomeric ratio (up to 99:1).

11.
PLoS Pathog ; 17(3): e1009392, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33760889

RESUMO

Coronavirus interaction with its viral receptor is a primary genetic determinant of host range and tissue tropism. SARS-CoV-2 utilizes ACE2 as the receptor to enter host cell in a species-specific manner. We and others have previously shown that ACE2 orthologs from New World monkey, koala and mouse cannot interact with SARS-CoV-2 to mediate viral entry, and this defect can be restored by humanization of the restrictive residues in New World monkey ACE2. To better understand the genetic determinants behind the ability of ACE2 orthologs to support viral entry, we compared koala and mouse ACE2 sequences with that of human and identified the key residues in koala and mouse ACE2 that restrict viral receptor activity. Humanization of these critical residues rendered both koala and mouse ACE2 capable of binding the spike protein and facilitating viral entry. Our study shed more lights into the genetic determinants of ACE2 as the functional receptor of SARS-CoV-2, which facilitates our understanding of viral entry.


Assuntos
/enzimologia , Peptidil Dipeptidase A/genética , Receptores Virais/genética , /fisiologia , Animais , Sequência de Bases , Especificidade de Hospedeiro , Humanos , Camundongos/genética , Camundongos/virologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Phascolarctidae/genética , Phascolarctidae/virologia , Receptores Virais/metabolismo , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
12.
Zhongguo Zhong Yao Za Zhi ; 46(4): 951-965, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33645102

RESUMO

The Qinling-Daba Mountains area is the main producing areas of Gynostemma longipes for medicinal usage, and samples of wild whole plants in Pingli, Shaanxi Province and Qingchuan, Sichuan Province were collected. The ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS~E) was used to profile the chemical compositions and analyze the similarities and differences of G. longipes samples in these areas. Based on the accurate molecular weight and fragment information obtained from Q-TOF-MS~E, the structures of the main components were identified by combining with the mass spectra, chromatographic behaviors of reference standards and related literatures. The results showed that the components of wild G. longipes from different places among Qinling-Daba Mountains area were similar. Forty-five chemical components were identified in the whole plant of G. longipes from Pingli, Shaanxi Province, including 43 triterpenoid saponins and 2 flavonoids which contain all main peaks in its fingerprint. The main components are dammarane-type triterpenoid saponins, such asgypenoside ⅩLⅨ, gypenoside A and its malonylated product of glycosyl.


Assuntos
Medicamentos de Ervas Chinesas , Saponinas , Cromatografia Líquida de Alta Pressão , Gynostemma , Espectrometria de Massas
13.
Emerg Microbes Infect ; 10(1): 700-709, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33739229

RESUMO

Bloodstream infections (BSIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) are potentially life-threatening and an urgent threat to public health. The present study aims to clarify the characteristics of carbapenemase-encoding and virulent plasmids, and their interactions with the host bacterium. A total of 425 Kp isolates were collected from the blood of BSI patients from nine Chinese hospitals, between 2005 and 2019. Integrated epidemiological and genomic data showed that ST11 and ST307 Kp isolates were associated with nosocomial outbreak and transmission. Comparative analysis of 147 Kp genomes and 39 completely assembled chromosomes revealed extensive interruption of acrR by ISKpn26 in all Kp carbapenemase-2 (KPC-2)-producing ST11 Kp isolates, leading to activation of the AcrAB-Tolc multidrug efflux pump and a subsequent reduction in susceptibility to the last-resort antibiotic tigecycline and six other antibiotics. We described 29 KPC-2 plasmids showing diverse structures, two virulence plasmids in two KPC-2-producing Kp, and two novel multidrug-resistant (MDR)-virulent plasmids. This study revealed a multifactorial impact of KPC-2 plasmid on Kp, which may be associated with nosocomial dissemination of MDR isolates.

14.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33658332

RESUMO

The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs-including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria-could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.


Assuntos
/genética , Receptores Virais/genética , /genética , /metabolismo , Animais , /metabolismo , Especificidade de Hospedeiro , Humanos , Pandemias/prevenção & controle , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Filogenia , Ligação Proteica , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Tropismo Viral , /prevenção & controle , Ligação Viral , Internalização do Vírus
15.
JAMA Netw Open ; 4(3): e211809, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33724394

RESUMO

Importance: There is a lack of studies exploring whether the survival of patients with distant lymph node metastases (DLNM) is different from that of patients with ipsilateral supraclavicular lymph node metastases (ISLM) and other stage IV breast cancer. Objective: To assess the survival of patients with DLNM from breast cancer vs ISLM and other stage IV breast cancer. Design, Setting, and Participants: This cohort study included 2033 patients diagnosed with breast cancer between January 1, 2010, and December 31, 2014, from the Surveillance, Epidemiology and End Results registries database. Three groups of patients were included: (1) patients with ISLM without any distant metastasis, (2) patients with DLNM, and (3) patients with distant metastases (DLNM excluded). Patients younger than 18 years or older than 100 years were excluded. The data were analyzed in February 2020. Exposures: Surgery for primary tumor, surgery for distant lymph nodes, and radiotherapy. Main Outcomes and Measures: Overall survival (OS) and breast cancer-specific survival (BCSS). Results: Of the 2033 women (mean [SD] age, 62.03 [14.62] years [range, 23.00-99.00 years]; 1510 White participants [74.3%]) with breast cancer included in the study, 346 patients (17.0%) had DLNM, 212 (10.4%) had ISLM, and 1475 (72.6%) had distant metastases (DLNM excluded). The 3-year BCSS rates were 63.24% for ISLM, 64.54% for DLNM, and 41.20% for distant metastases. The 3-year OS rates were 53.46% for ISLM, 62.67% for DLNM, and 38.21% for distant metastases. Compared with patients with ISLM, patients with DLNM showed similar BCSS (hazard ratio [HR], 0.81; 95% CI, 0.52-1.25; P = .34) and OS (HR, 0.73; 95% CI, 0.51-1.05; P = .09), whereas patients with distant metastases showed significantly poorer BCSS (HR, 1.99; 95% CI, 1.43-2.78; P < .001) and OS (HR, 1.79; 95% CI, 1.35-2.38; P < .001). Of the 346 patients with DLNM, primary surgery (HR, 0.21; 95% CI, 0.12-0.39; P < .001) and radiotherapy (HR, 0.46; 95% CI, 0.25-0.87; P = .02) were significantly associated with improved OS. Conclusions and Relevance: The results of this cohort study suggest that DLNM of breast cancer, with similar survival to N3c disease (indicating metastases to the ipsilateral supraclavicular lymph nodes), might be a regional disease, and reassessment of the role of lymph node metastases in breast cancer may be necessary. Given these findings, aggressive locoregional therapies for this disease are recommended, although future studies are still needed to confirm these results.


Assuntos
Neoplasias da Mama/mortalidade , Sistema de Registros , Programa de SEER , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/secundário , China/epidemiologia , Clavícula , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Adulto Jovem
16.
Nat Commun ; 12(1): 961, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574281

RESUMO

The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.


Assuntos
/virologia , Sistemas CRISPR-Cas , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , Internalização do Vírus , Células A549 , /metabolismo , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Endossomos/virologia , Células HeLa , Humanos , Mesocricetus , Serina Endopeptidases , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
17.
Small ; 17(8): e2006599, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33522150

RESUMO

Invoking the occurrence of pyroptosis is an emerging strategy for the treatment of cancer. However, the practical applications of pyroptosis for cancer therapy are currently hindered due to the lack of tumor-specific and efficient pyroptotic agents in vivo. Herein, a virus-spike tumor-activatable pyroptotic agent (VTPA) for cancer-specific therapy is reported. The VTPA is composed of an organosilica coated iron oxide nanoparticle core and spiky manganese dioxide protrusions, which can readily accumulate in tumor after systemic administration, facilitate the tumor intracellular lysosomal rupture, and be degraded by tumor over-expressed intracellular glutathione (GSH) to release Mn ions and iron oxide nanoparticles (IONPs) for the synergetic activation of nucleotide binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasomes. Consequently, the activation of NLRP3 inflammasomes and the release of lactate dehydrogenase of tumor cells are observed after the treatment of VTPA, resulting in a specific pyroptotic cell death. To our best knowledge, the structure-dependent and tumor intracellular GSH activatable pyroptotic agents represent the first demonstration of cancer-specific pyroptosis in vivo, providing a novel paradigm for the development of next-generation cancer-specific pyroptotic nanomedicine.

18.
Sci Adv ; 7(2)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523994

RESUMO

Hepatitis C virus (HCV) remains a major human pathogen that requires better understanding of virus-host interactions. In this study, we performed a genome-wide CRISPR-Cas9 screening and identified TRIM26, an E3 ligase, as a critical HCV host factor. Deficiency of TRIM26 specifically impairs HCV genome replication. Mechanistic studies showed that TRIM26 interacts with HCV-encoded NS5B protein and mediates its K27-linked ubiquitination at residue K51, and thus promotes the NS5B-NS5A interaction. Moreover, mouse TRIM26 does not support HCV replication because of its unique six-amino acid insert that prevents its interaction with NS5B. Ectopic expression of human TRIM26 in a mouse hepatoma cell line that has been reconstituted with other essential HCV host factors promotes HCV infection. In conclusion, we identified TRIM26 as a host factor for HCV replication and a new determinant of host tropism. These results shed light on HCV-host interactions and may facilitate the development of an HCV animal model.

19.
Microb Drug Resist ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33570473

RESUMO

As a potential "Superbug," Pseudomonas aeruginosa remains the leading concern in antimicrobial resistance. In this study, the emergence of clinical P. aeruginosa isolate was found to carry crpP and blaGES-5 on the chromosome and blaKPC-2 on a plasmid. A clinical P. aeruginosa strain Guangzhou-PaeC79 with an extensively drug-resistant phenotype was isolated, which was resistant to all classes of clinical commonly used antibiotics. It contains one chromosomal DNA and one plasmid, with seven acquired antimicrobial resistance genes identified on the chromosome, including carbapenem resistance gene blaGES-5 and fluoroquinolone resistance gene crpP, and carbapenem resistance gene blaKPC-2 located on an IncP-6-type plasmid pPAEC79 carrying a Tn3-like element. Carriage of any two of the resistance genes has never been previously reported, and simultaneous carriage of three bla and crpP may explain the bacterial phenotype as high-level resistance to imipenem and meropenem (≥16 µg/mL) and resistance to ciprofloxacin and levofloxacin.

20.
Anim Biotechnol ; : 1-7, 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33583337

RESUMO

Keratin-associated proteins (KAPs) are important structural components of fibers that predominantly present in the ortho-cortex. These proteins form a cross-linked network with keratin intermediate filaments (KIFs), thus producing a strong hair shaft. The keratin-associated protein 6-1 gene (KAP6-1) is a member of the KAPs family that has a potential correlation with fiber traits. In this study, we investigated the influence of KAP6-1 sequence polymorphisms on the fiber characteristics of a Chinese cashmere-producing goat breed (n = 844). Two main variants were found, including a three base pair (bp) deletion (namely B) and a 36-bp deletion (namely C), while the reference genotype of KAP6-1 was named A. Among them, the B variant was first reported on cashmere goats. This study then correlated these genotypes with the collected fiber data to investigate the potential association of these variants. The results showed that variant A is associated with decreased fiber diameter (p < 0.01), while variant C is associated with deceased fiber length (p < 0.01). These two related variants of the KAP6-1 gene have potential applications as gene-makers to improve the fiber diameter and length in cashmere-producing goats.

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