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1.
Proc Natl Acad Sci U S A ; 118(16)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33853942

RESUMO

Host-derived fatty acids are an important carbon source for pathogenic mycobacteria during infection. How mycobacterial cells regulate the catabolism of fatty acids to serve the pathogenicity, however, remains unknown. Here, we identified a TetR-family transcriptional factor, FdmR, as the key regulator of fatty acid catabolism in the pathogen Mycobacterium marinum by combining use of transcriptomics, chromatin immunoprecipitation followed by sequencing, dynamic 13C-based flux analysis, metabolomics, and lipidomics. An M. marinum mutant deficient in FdmR was severely attenuated in zebrafish larvae and adult zebrafish. The mutant showed defective growth but high substrate consumption on fatty acids. FdmR was identified as a long-chain acyl-coenzyme A (acyl-CoA)-responsive repressor of genes involved in fatty acid degradation and modification. We demonstrated that FdmR functions as a valve to direct the flux of exogenously derived fatty acids away from ß-oxidation toward lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. Moreover, we found that FdmR suppresses degradation of long-chain acyl-CoAs endogenously synthesized through the type I fatty acid synthase. By modulating the supply of long-chain acyl-CoAs for lipogenesis, FdmR controls the abundance and chain length of virulence-associated lipids and mycolates and plays an important role in the impermeability of the cell envelope. These results reveal that despite the fact that host-derived fatty acids are used as an important carbon source, overactive catabolism of fatty acids is detrimental to mycobacterial cell growth and pathogenicity. This study thus presents FdmR as a potentially attractive target for chemotherapy.

2.
Chin J Nat Med ; 19(2): 90-99, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33641788

RESUMO

This study was to investigate the protective effect of paeoniflorin (PF) on hydrogen peroxide-induced injury. Firstly, "SMILES" of PF was searched in Pubchem and further was used for reverse molecular docking in Swiss Target Prediction database to obtain potential targets. Injury-related molecules were obtained from GeenCards database, and the predicted targets of PF for injury treatment were selected by Wayne diagram. For mechanism analysis, the protein-protein interactions were constructed by String, and the KEGG analysis was conducted in Webgestalt. Then, cell viability and cytotoxicity assay were established by CCK8 assay. Also, the experimental cells were allocated to control, model (200 µmol·L-1 H2O2), SB203580 10 µmol·L-1 (200 µmol·L-1 H2O2+ SB203580 10 µmol·L-1), PF 50 µmol·L-1 (200 µmol·L-1 H2O2+ PF 50 µmol·L-1), and PF 100 µmol·L-1 (200 µmol·L-1 H2O2+ PF 100 µmol·L-1) groups. We measured the intracellular ROS, Hoechst 33258 staining, cell apoptosis, the levels of Bcl-xl, Bcl-2, Caspase-3, Cleaved-caspase3, Cleaved-caspase7, TRPA1, TRPV1, and the phosphorylation expression of p38MAPK. There are 96 potential targets that may be associated with PF for injury treatment. Then, we chose the "Inflammatory mediator regulation of TRP channels" pathway for the experimental verification from the first 10 KEGG pathway. In experimental verification, H2O2 decreased the cell viability moderately (P < 0.05), and 100 µmol·L -1 PF increased the cell viability significantly (P < 0.05). Depending on the difference of intracellular ROS fluorescence intensity, PF inhibited H 2O2-induced reactive oxygen species production in Schwann cells. In Hoechst 33258 staining, PF reversed the condensed chromatin and apoptotic nuclei following H2O2 treatment. Moreover, Flow cytometry results showed that PF could substantially inhibit H2O2 induced apoptosis (P < 0.05). Pretreatment with PF obviously reduced the levels of Caspase3, Cleaved-caspase3, Cleaved-caspase7, TRPA1, TRPV1, and the phosphorylation expression of p38MAPK after H 2O2 treatment (P < 0.05), increased the levels of Bcl-2, and Bcl-xl ( P < 0.05). PF inhibited Schwann cell injury and apoptosis induced by hydrogen peroxide, which mechanism was linked to the inhibition of phosphorylation of p38MAPK.

3.
Sci Bull (Beijing) ; 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33585048

RESUMO

The pandemic due to the SARS-CoV-2 virus, the etiological agent of Coronavirus Disease 2019 (COVID-19), has caused immense global disruption. With the rapid accumulation of SARS-CoV-2 genome sequences, however, thousands of genomic variants of SARS-CoV-2 are now publicly available. To improve the tracing of the viral genomes' evolution during the development of the pandemic, we analyzed single nucleotide variants (SNVs) in 121,618 high-quality SARS-CoV-2 genomes. We divided these viral genomes into two major lineages (L and S) based on variants at sites 8782 and 28144, and further divided the L lineage into two major sublineages (L1 and L2) using SNVs at sites 3037, 14408, and 23403. Subsequently, we categorized them into 130 sublineages (37 in S, 35 in L1, and 58 in L2) based on marker SNVs at 201 additional genomic sites. This lineage/sublineage designation system has a hierarchical structure and reflects the relatedness among the subclades of the major lineages. We also provide a companion website (www.covid19evolution.net) that allows users to visualize sublineage information and upload their own SARS-CoV-2 genomes for sublineage classification. Finally, we discussed the possible roles of compensatory mutations and natural selection during SARS-CoV-2's evolution. These efforts will improve our understanding of the temporal and spatial dynamics of SARS-CoV-2's genome evolution.

4.
Nat Commun ; 12(1): 1075, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597544

RESUMO

Understanding ecological niches of major tick species and prevalent tick-borne pathogens is crucial for efficient surveillance and control of tick-borne diseases. Here we provide an up-to-date review on the spatial distributions of ticks and tick-borne pathogens in China. We map at the county level 124 tick species, 103 tick-borne agents, and human cases infected with 29 species (subspecies) of tick-borne pathogens that were reported in China during 1950-2018. Haemaphysalis longicornis is found to harbor the highest variety of tick-borne agents, followed by Ixodes persulcatus, Dermacentor nutalli and Rhipicephalus microplus. Using a machine learning algorithm, we assess ecoclimatic and socioenvironmental drivers for the distributions of 19 predominant vector ticks and two tick-borne pathogens associated with the highest disease burden. The model-predicted suitable habitats for the 19 tick species are 14‒476% larger in size than the geographic areas where these species were detected, indicating severe under-detection. Tick species harboring pathogens of imminent threats to public health should be prioritized for more active field surveillance.


Assuntos
Infestações por Carrapato/epidemiologia , Doenças Transmitidas por Carrapatos/epidemiologia , Carrapatos/crescimento & desenvolvimento , Animais , China/epidemiologia , Análise por Conglomerados , Geografia , Incidência , Especificidade da Espécie , Infestações por Carrapato/parasitologia , Doenças Transmitidas por Carrapatos/parasitologia , Carrapatos/classificação , Carrapatos/fisiologia
5.
Ecotoxicol Environ Saf ; 210: 111903, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33429322

RESUMO

A diverse and large community of gut microbiota reside in the intestinal tract of various organisms and play important roles in metabolism and immune homeostasis of its host. The disorders of microbiota-host interaction have been closely associated with numerous chronic inflammatory and metabolic diseases, including inflammatory bowel disease and type 2 diabetes. The accumulating evidence has shown that fine particulate matter (PM2.5) exposure contributes to the diabetes, atherosclerosis and inflammatory bowel diseases; however, few studies have explored the impact of inhaled diesel PM2.5 on gut microbiota in vivo. In this study, C57BL/6J mice were exposed to diesel PM2.5 for 14 days via intratracheal instillation, and colon tissues and feces were harvested for microbiota analysis. Using high-throughput sequencing technology, we observed that intratracheally instillated diesel PM2.5 significantly altered the gut microbiota diversity and community. At the phylum and genus levels, principal coordinate analysis (PCoA) and principal component analysis (PCA) indicated pronounced segregation of microbiota compositions, which were further confirmed by ß diversity analysis. As the most affected phylum, Bacteroidetes was greatly diminished by diesel PM2.5. On the genus level, Escherichia, Parabacteroides, Akkermansia, and Oscillibacter were significantly elevated by diesel PM2.5 exposure. Our findings provided clear evidence that exposure to diesel PM2.5 via intratracheal instillation deteriorated the gastrointestinal (GI) tract and significantly altered the structure and composition of gut microbiota, which might subsequently contribute to the developmental abnormalities of inflammation, immunity and metabolism.


Assuntos
Poluentes Atmosféricos/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Material Particulado/toxicidade , Administração por Inalação , Animais , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL
6.
Int J Infect Dis ; 103: 540-548, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33310028

RESUMO

OBJECTIVES: This study intended to investigate the dynamics of anti-spike (S) IgG and IgM antibodies in COVID-19 patients. METHODS: Anti-S IgG/IgM was determined by a semi-quantitative fluorescence immunoassay in the plasma of COVID-19 patients at the manifestation and rehabilitation stages. The immunoreactivity to full-length S proteins, C-terminal domain (CTD), and N-terminal domain (NTD) of S1 fragments were determined by an ELISA assay. Clinical properties at admission and discharge were collected simultaneously. RESULTS: The positive rates of anti-S IgG/IgM in COVID-19 patients were elevated after rehabilitation compared to the in-patients. Anti-S IgG and IgM were not apparent until day 14 and day ten, respectively, according to Simple Moving Average analysis with five days' slide window deduction. More than 90% of the rehabilitation patients exhibited IgG and IgM responses targeting CTD-S1 fragments. Decreased total peripheral lymphocytes, CD4+ and CD8+ T cell counts were seen in COVID-19 patients at admission and recovered after the rehabilitation. CONCLUSIONS: Anti-S IgG and IgM do not appear at the onset with the decrease in T cells, making early serological screening less significant. However, the presence of high IgG and IgM to S1-CTD in the recovered patients highlights humoral responses after SARS-CoV-2 infection, which might be associated with efficient immune protection in COVID-19 patients.


Assuntos
Anticorpos Antivirais/sangue , /imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade
7.
Front Immunol ; 11: 576603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329543

RESUMO

Introduction and Objective: Neoantigen-based immunotherapy is one of the breakthroughs in cancer immunotherapy. Benefit from the Cancer Genome Atlas database, we intended to identify mutant peptides with neoantigen property in bladder cancer (BC). Correlations between the immunoreactivity of candidate neoantigens and clinical manifestations were further analyzed. Methods: HLA-A*02:01 restricted mutant (MT) and wildtype (WT) peptides were predicted by using whole exome sequencing data of 412 BC patients in the TCGA database. Binding affinity to HLA-A2 molecules was determined by using T2 cell-based binding assay. The immunoreactivity to WT and MT peptides in HLA-A2+ BC patients was determined by using an ELISPOT assay upon in vitro stimulation with MT and WT peptides individually. Clinical relevance to peptide-specific immunoreactivity was analyzed by Pearson correlation analysis. The disease free survival (DFS) curves were plotted using the Kaplan-Meier method in BC patients with or without mutations and compared using the log-rank test online. Results: Fifty-seven HLA-A*02:01 restricted WT and MT peptides were selected based on predicted high affinity and expression frequency, among which 12 MT peptides from 12 individual genes exhibited strong affinity to HLA-A2 molecules when compared to WT counterparts. MT peptides induced more peptide-specific IFNγ spot forming units (SFUs) than WT counterparts in HLA-A2+ BC patients upon in vitro stimulation. They were negatively correlated to the counts of peripheral leukocytes and platelets. Patients with higher C-reactive protein level exhibited lower immunoreactivity to MT peptides. Combination of MT peptides from 6 genes, including CDKN1AG61V , RHOBP75L , DDB1S25L , AHNAKD4855Y , ANP32AS56L and MKI67H84L covered 47.5% of the patients under investigation. Patients harboring combinational mutations in these genes were associated with a longer DFS according to the cBioportal online analysis. Conclusion: Twelve HLA-A*02:01 restricted MT peptides have been identified exhibiting higher binding affinity to HLA-A2 molecules and stronger immunoreactivity than WT counterparts in BC patients. Combination of MT peptides from six genes might be potential as neoantigen candidates in cancer immunotherapy against BC in the future. Inflammatory modulation is inclined to be a strategy to enhance the efficacy of neoantigen-based immunotherapy.

8.
EBioMedicine ; 61: 103036, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33045467

RESUMO

BACKGROUND: Real-time reverse transcription-PCR (rRT-PCR) has been the most effective and widely implemented diagnostic technology since the beginning of the COVID-19 pandemic. However, fuzzy rRT-PCR readouts with high Ct values are frequently encountered, resulting in uncertainty in diagnosis. METHODS: A Specific Enhancer for PCR-amplified Nucleic Acid (SENA) was developed based on the Cas12a trans-cleavage activity, which is specifically triggered by the rRT-PCR amplicons of the SARS-CoV-2 Orf1ab (O) and N fragments. SENA was first characterized to determine its sensitivity and specificity, using a systematic titration experiment with pure SARS-CoV-2 RNA standards, and was then verified in several hospitals, employing a couple of commercial rRT-PCR kits and testing various clinical specimens under different scenarios. FINDINGS: The ratio (10 min/5 min) of fluorescence change (FC) with mixed SENA reaction (mix-FCratio) was defined for quantitative analysis of target O and N genes, and the Limit of Detection (LoD) of mix-FCratio with 95% confidence interval was 1.2≤1.6≤2.1. Totally, 295 clinical specimens were analyzed, among which 21 uncertain rRT-PCR cases as well as 4 false negative and 2 false positive samples were characterized by SENA and further verified by next-generation sequencing (NGS). The cut-off values for mix-FCratio were determined as 1.145 for positive and 1.068 for negative. INTERPRETATION: SENA increases both the sensitivity and the specificity of rRT-PCR, solving the uncertainty problem in COVID-19 diagnosis and thus providing a simple and low-cost companion diagnosis for combating the pandemic. FUNDING: Detailed funding information is available at the end of the manuscript.


Assuntos
Proteínas de Bactérias/metabolismo , Betacoronavirus/genética , Proteínas Associadas a CRISPR/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Endodesoxirribonucleases/metabolismo , RNA Viral/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Limite de Detecção , Cavidade Nasal/virologia , Técnicas de Amplificação de Ácido Nucleico/métodos , Técnicas de Amplificação de Ácido Nucleico/normas , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , Pandemias , Fosfoproteínas , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Poliproteínas , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real/normas , Padrões de Referência , Proteínas Virais/genética , Proteínas Virais/metabolismo
9.
Clin Infect Dis ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33068430

RESUMO

BACKGROUND: The growing epidemics of severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne disease in East Asia, and its high case fatality rate have raised serious public health concerns. METHODS: Surveillance data on laboratory-confirmed SFTS cases in China were collected. The spatiotemporal dynamics and epidemiological features were explored. The socioeconomic and environmental drivers were identified for SFTS diffusion using survival analysis and for SFTS persistence using a two-stage generalized boosted regression tree model. RESULTS: During 2010‒2018, a total of 7,721 laboratory-confirmed SFTS cases were reported in China, with an overall CFR of 10.5%. The average annual incidence increased >20 times and endemic areas expanded from 27 to 1,574 townships, whereas the CFR declined from 19% to 10% during this period. Four geographical clusters, the Changbai Mountain area, the Jiaodong Peninsula, the Taishan Mountain area and the Huaiyangshan Mountain area, were identified. Diffusion and persistence of the disease were both driven by elevation, high coverages of woods, crops and shrub, and the vicinity of habitats of migratory birds, but had different meteorological drivers. Residents ≥60 years old in rural areas with crop fields and tea farms were at increased risk to SFTS. CONCLUSIONS: Surveillance of SFTS and intervention programs need to be targeted at areas with ecologically suitability for vector ticks and in the vicinity of migratory birds to curb the growing epidemic.

10.
Front Genet ; 11: 960, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014019

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor. Radiotherapy (RT) is an important treatment for HNSCC, but not all patients derive survival benefit from RT due to the individual differences on radiosensitivity. A prediction model of radiosensitivity based on multiple omics data might solve this problem. Compared with single omics data, multiple omics data can illuminate more systematical associations between complex molecular characteristics and cancer phenotypes. In this study, we obtained 122 differential expression genes by analyzing the gene expression data of HNSCC patients with RT (N = 287) and without RT (N = 189) downloaded from The Cancer Genome Atlas. Then, HNSCC patients with RT were randomly divided into a training set (N = 149) and a test set (N = 138). Finally, we combined multiple omics data of 122 differential genes with clinical outcomes on the training set to establish a 12-gene signature by two-stage regularization and multivariable Cox regression models. Using the median score of the 12-gene signature on the training set as the cutoff value, the patients were divided into the high- and low-score groups. The analysis revealed that patients in the low-score group had higher radiosensitivity and would benefit from RT. Furthermore, we developed a nomogram to predict the overall survival of HNSCC patients with RT. We compared the prognostic value of 12-gene signature with those of the gene signatures based on single omics data. It suggested that the 12-gene signature based on multiple omics data achieved the best ability for predicting radiosensitivity. In conclusion, the proposed 12-gene signature is a promising biomarker for estimating the RT options in HNSCC patients.

11.
Int J Mol Sci ; 21(18)2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32932732

RESUMO

Radiotherapy is an important modality for the local control of human cancers, but the radioresistance induced by aberrant apoptotic signaling is a hallmark of cancers. Restoring the aberrant apoptotic pathways is an emerging strategy for cancer radiotherapy. In this study, we determined that targeting cell division cycle 20 (CDC20) radiosensitized colorectal cancer (CRC) cells through mitochondrial-dependent apoptotic signaling. CDC20 was overexpressed in CRC cells and upregulated after radiation. Inhibiting CDC20 activities genetically or pharmacologically suppressed the proliferation and increased radiation-induced DNA damage and intrinsic apoptosis in CRC cells. Mechanistically, knockdown of CDC20 suppressed the expression of antiapoptotic protein Mcl-1 but not other Bcl-2 family proteins. The expressions of CDC20 and Mcl-1 respond to radiation simultaneously through direct interaction, as evidenced by immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Subsequently, decreased Mcl-1 expression inhibited the expression level of phosphorylated checkpoint kinase 1 (p-Chk1), thereby resulting in impaired DNA damage repair through downregulating the homologous recombination repair protein Rad51 and finally causing apoptotic signaling. In addition, both CDC20 and Chk1 inhibitors together, through in vivo studies, confirmed the radiosensitizing effect of CDC20 via inhibiting Mcl-1 and p-Chk1 expression. In summary, our results indicate that targeting CDC20 is a promising strategy to improve cancer radiotherapy.

12.
Sci Rep ; 10(1): 15394, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958789

RESUMO

More than 150 ginsenosides have been isolated and identified from Panax plants. Ginsenosides with different glycosylation degrees have demonstrated different chemical properties and bioactivity. In this study, we systematically cloned and characterized 46 UGT94 family UDP-glycosyltransferases (UGT94s) from a mixed Panax ginseng/callus cDNA sample with high amino acid identity. These UGT94s were found to catalyze sugar chain elongation at C3-O-Glc and/or C20-O-Glc of protopanaxadiol (PPD)-type, C20-O-Glc or C6-O-Glc of protopanaxatriol (PPT)-type or both C3-O-Glc of PPD-type and C6-O-Glc of PPT-type or C20-O-Glc of PPD-type and PPT-type ginsenosides with different efficiencies. We also cloned 26 and 51 UGT94s from individual P. ginseng and P. notoginseng plants, respectively; our characterization results suggest that there is a group of UGT94s with high amino acid identity but diverse functions or catalyzing activities even within individual plants. These UGT94s were classified into three clades of the phylogenetic tree and consistent with their catalytic function. Based on these UGT94s, we elucidated the biosynthetic pathway of a group of ginsenosides. Our present results reveal a series of UGTs involved in second sugar chain elongation of saponins in Panax plants, and provide a scientific basis for understanding the diverse evolution mechanisms of UGT94s among plants.

13.
Microb Cell Fact ; 19(1): 180, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933531

RESUMO

BACKGROUND: Epothilone B is a natural product that stabilizes microtubules, similar to paclitaxel (Taxol); therefore, epothilone B and several derivatives have shown obvious antitumour activities. Some of these products are in clinical trials, and one (ixabepilone, BMS) is already on the market, having been approved by the FDA in 2007. The terminal step in epothilone B biosynthesis is catalysed by the cytochrome P450 enzyme EpoK (CYP167A1), which catalyses the epoxidation of the C12-C13 double bond (in epothilone C and D) to form epothilone A and B, respectively. Although redox partners from different sources support the catalytic activity of EpoK in vitro, the conversion rates are low, and these redox partners are not applied to produce epothilone B in heterologous hosts. RESULTS: Schlegelella brevitalea DSM 7029 contains electron transport partners that efficiently support the catalytic activity of EpoK. We screened and identified one ferredoxin, Fdx_0135, by overexpressing putative ferredoxin genes in vivo and identified two ferredoxin reductases, FdR_0130 and FdR_7100, by whole-cell biotransformation of epothilone C to effectively support the catalytic activity of EpoK. In addition, we obtained strain H7029-3, with a high epothilone B yield and found that the proportion of epothilone A + B produced by this strain was 90.93%. Moreover, the whole-cell bioconversion strain 7029-10 was obtained; this strain exhibited an epothilone C conversion rate of 100% in 12 h. Further RT-qPCR experiments were performed to analyse the overexpression levels of the target genes. Gene knock-out experiments showed that the selected ferredoxin (Fdx_0135) and its reductases (FdR_0130 and FdR_7100) might participate in critical physiological processes in DSM 7029. CONCLUSION: Gene overexpression and whole-cell biotransformation were effective methods for identifying the electron transport partners of the P450 enzyme EpoK. In addition, we obtained an epothilone B high-yield strain and developed a robust whole-cell biotransformation system. This strain and system hold promise for the industrial production of epothilone B and its derivatives.

14.
Environ Toxicol Chem ; 39(10): 1884-1893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32936472

RESUMO

Neonicotinoids are a widely used class of pesticides. Co-exposure to neonicotinoids and other classes of pesticides can exert potentiating or synergistic effects, and these mixtures have been detected in human bodily fluids. The present review summarizes studies into the effects of neonicotinoid-containing pesticide mixtures on humans and other nontarget organisms. Exposure to these mixtures has been reported to result in reproductive and hormonal toxicity, genotoxicity, neurotoxicity, hepatotoxicity, and immunotoxicity in vertebrates. Mortality of pollinators and toxicity in other organisms has also been reported. The underlying mechanism of pesticide mixture toxicity may be associated with impairment of cytochrome 450 enzymes, which are involved in metabolizing pesticides. However, a comprehensive explanation of the adverse effects of neonicotinoid-containing pesticide mixtures is still required so that effective prevention and control measures can be formulated. Environ Toxicol Chem 2020;39:1884-1893. © 2020 SETAC.

15.
PLoS One ; 15(9): e0239148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936793

RESUMO

Lower limb exoskeletons and lower limb prostheses have the potential to reduce gait limitations during stair ambulation. To develop robotic assistance devices, the biomechanics of stair ambulation and the required transitions to level walking have to be understood. This study aimed to identify the timing of these transitions, to determine if transition phases exist and how long they last, and to investigate if there exists a joint-related order and timing for the start and end of the transitions. Therefore, this study analyzed the kinematics and kinetics of both transitions between level walking and stair ascent, and between level walking and stair descent (12 subjects, 25.4 yrs, 74.6 kg). We found that transitions primarily start within the stance phase and end within the swing phase. Transition phases exist for each limb, all joints (hip, knee, ankle), and types of transitions. They have a mean duration of half of one stride and they do not last longer than one stride. The duration of the transition phase for all joints of a single limb in aggregate is less than 35% of one stride in all but one case. The distal joints initialize stair ascent, while the proximal joints primarily initialize the stair descent transitions. In general, the distal joints complete the transitions first. We believe that energy- and balance-related processes are responsible for the joint-specific transition timing. Regarding the existence of a transition phase for all joints and transitions, we believe that lower limb exoskeleton or prosthetic control concepts should account for these transitions in order to improve the smoothness of the transition and to thus increase the user comfort, safety, and user experience. Our gait data and the identified transition timings can provide a reference for the design and the performance of stair ambulation- related control concepts.


Assuntos
Articulação do Tornozelo/fisiologia , Marcha/fisiologia , Articulação do Quadril/fisiologia , Articulação do Joelho/fisiologia , Subida de Escada/fisiologia , Adulto , Membros Artificiais , Fenômenos Biomecânicos/fisiologia , Exoesqueleto Energizado , Humanos , Extremidade Inferior , Masculino , Equilíbrio Postural/fisiologia , Desenho de Prótese/métodos , Amplitude de Movimento Articular/fisiologia , Fatores de Tempo , Adulto Jovem
16.
Adv Mater ; : e1907452, 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32743868

RESUMO

Magnetic skyrmions are attracting interest as efficient information-storage devices with low energy consumption, and have been experimentally and theoretically investigated in multilayers including ferromagnets, ferrimagnets, and antiferromagnets. The 3D spin texture of skyrmions demonstrated in ferromagnetic multilayers provides a powerful pathway for understanding the stabilization of ferromagnetic skyrmions. However, the manipulation mechanism of skyrmions in antiferromagnets is still lacking. A Hall balance with a ferromagnet/insulating spacer/ferromagnet structure is considered to be a promising candidate to study skyrmions in synthetic antiferromagnets. Here, high-density Néel-type skyrmions are experimentally observed at zero field and room temperature by Lorentz transmission electron microscopy in a Hall balance (core structure [Co/Pt]n /NiO/[Co/Pt]n ) with interfacial canted magnetizations because of interlayer ferromagnetic/antiferromagnetic coupling between top and bottom [Co/Pt]n multilayers, where the Co layers in [Co/Pt]n are always ferromagnetically coupled. Micromagnetic simulations show that the generation and density of skyrmions are strongly dependent on interlayer exchange coupling (IEC) and easy-axis orientation. Direct experimental evidence of skyrmions in synthetic antiferromagnets is provided, suggesting that the proposed approach offers a promising alternative mechanism for room-temperature spintronics.

17.
ACS Synth Biol ; 9(8): 2009-2022, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32603592

RESUMO

Epothilones, as a new class of microtubule-stabilizing anticancer drugs, exhibit strong bioactivity against taxane-resistant cells and show clinical activity for the treatment of advanced breast cancer. Additionally, they also show great potential for a central nervous system injury and Alzheimer's disease. However, due to the long fermentation period of the original producer and challenges of genetic engineering of nonribosomal peptide/polyketide (NRP/PK) megasynthase genes, the application of epothilones is severely limited. Here, we addressed these problems by reassembling a novel 56-kb epothilone biosynthetic gene cluster, optimizing the promoter of each gene based on RNA-seq profiling, and completing precursor synthetic pathways in engineered Schlegella brevitalea. Furthermore, we debottlenecked the cell autolysis by optimizing culture conditions. Finally, the yield of epothilones in shake flasks was improved to 82 mg/L in six-day fermentation. Overall, we not only constructed epothilone overproducers for further drug development but also provided a rational strategy for high-level NRP/PK compound production.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32617100

RESUMO

Background: Hederagenin is one of the main components of Tetrapanax papyriferus, and Tetrapanax papyriferus is one of the ingredients of Danggui Sini decoction. To explore whether Tetrapanax papyriferus and hederagenin can alleviate mechanical pain, thermal hyperalgesia, and cold pain at the same time, we comprehensively investigated the effects of two drugs on the levels of p38 MAPK phosphorylation, TRP proteins, and IL1ß, IL6, and TNF-α in serum. Methods: Firstly, we obtained pain-related targets and performed KEGG pathway enrichment on these targets. Then, 42 SD rats were separated randomly into six groups: sham operation group, CCI group, pregabalin group, mecobalamin group, Tetrapanax papyriferus group, and hederagenin group. All drugs were given orally. Rats in the sham operation group and CCI group were gavaged with saline. Rats in the pregabalin group were given pregabalin, while rats in the mecobalamin group were given mecobalamin. Rats in the Tetrapanax papyriferus group were given Tetrapanax papyriferus, while rats in the hederagenin group were given hederagenin. Besides, we conducted behavioral tests including acetone test, hot plate experiment, and von Frey filaments, and then dorsal root ganglion neurons were taken out on the 21st day after operation. Then, western blot, ELISA, and hematoxylin-eosin staining were conducted. Results: Rats in the CCI group were more sensitive to hyperalgesia and allodynia to mechanical and thermal stimuli, as well as cold pain. All four drugs could relieve these pains. Pregabalin, mecobalamin, and Tetrapanax papyriferus can reduce the levels of IL1ß, IL6, and TNF-α in serum compared to those of the CCI group. The expression of TRPM8, TRPA1, TRPV1, TRPV4, and phosphorylated p38 MAPK in DRG increased evidently on the 21st day after the operation in the CCI group. All four drugs could reduce the expressions of TRPM8, TRPA1, TRPV1, TRPV4, and phosphorylated p38 MAPK in dorsal root ganglion compared to those of the CCI group. Conclusion: Tetrapanax papyriferus and hederagenin relieved sciatica by reducing inflammation levels, inhibiting p38 MAPK phosphorylation, and decreasing the levels of dorsal root ganglion proteins.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32671053

RESUMO

Amycolatopsis mediterranei U32 is an industrial producer of rifamycin SV, whose derivatives have long been the first-line antimycobacterial drugs. In order to perform genetic modification in this important industrial strain, a lot of efforts have been made in the past decades and a homologous recombination-based method was successfully developed in our laboratory, which, however, requires the employment of an antibiotic resistance gene for positive selection and did not support convenient markerless gene deletion. Here in this study, the clustered regularly interspaced short palindromic repeat (CRISPR) system was employed to establish a genome editing system in A. mediterranei U32. Specifically, the Francisella tularensis subsp. novicida Cas12a (FnCas12a) gene was first integrated into the U32 genome to generate target-specific double-stranded DNA (dsDNA) breaks (DSBs) under the guidance of CRISPR RNAs (crRNAs). Then, the DSBs could be repaired by either the non-homologous DNA end-joining (NHEJ) system or the homology-directed repair (HDR) pathway, generating inaccurate or accurate mutations in target genes, respectively. Besides of A. mediterranei, the present work may also shed light on the development of CRISPR-assisted genome editing systems in other species of the Amycolatopsis genus.

20.
Front Cell Dev Biol ; 8: 408, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32596239

RESUMO

Radiotherapy is an essential curative treatment modality for colorectal cancer. Apoptosis is the major mechanism of IR-induced cell death and aberrant apoptotic signaling results in radioresistance, which is a hallmark of most, perhaps all, types of human cancers. Potentiating the induction of apoptosis is an emerging strategy for cancer radiotherapy. Here, we determined that targeting CDK8 selectively radiosensitized colorectal cancer through the mitochondria-dependent intrinsic apoptotic signaling, which was mediated through the induction of the transcription of apaf1 that was e2f1- and not p53-dependent. Importantly, the enhanced transcriptional activity of e2f1 was dependent on the kinase activity of CDK8 itself and not on the assembling of the mediator complex. In addition, clinical inhibitor, and in vivo studies confirmed the radiosensitizing effect of CDK8. Our results provide a new targeting strategy to improve the radiotherapy of CRC.

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