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2.
J Chromatogr A ; 1644: 462068, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33836299

RESUMO

Benzimidazoles, commonly used as pesticides and veterinary drugs, have posed a threat to human health and the environment due to unreasonable use and lack of valid regulation. Therefore, an up-to-date and comprehensive summary of the pretreatment and analytical approaches in different substrates is urgently needed. The present review consequently updates and covers various newly developed pretreatment methods (e.g., cationic micellar precipitation, magnetic-solid phase extraction, hollow fiber liquid phase microextraction, disperse liquid-liquid microextraction-solidified floating organic drop, stir cake sorptive extraction, solid phase microextraction method, QuEChERS, and molecular imprinted polymer-based methods) since 2005. The review also elaborates and discusses different determination methods (e.g., newly developed HPLC and related methods, improved spectrofluorimetry methods, capillary electrophoresis, and the electrochemical sensor). Furthermore, some critical points and prospects are highlighted, to describe the trends in this area.


Assuntos
Métodos Analíticos de Preparação de Amostras , Benzimidazóis/análise , Benzimidazóis/química , Humanos , Líquidos Iônicos/química , Microextração em Fase Líquida , Extração em Fase Sólida , Microextração em Fase Sólida
4.
J Biol Chem ; : 100538, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33722610

RESUMO

The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) and molecular dynamics (MD) simulations to investigate this question. We identify a partially-open, semi-active conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a "multiple gear" regulatory mechanism, in which different activators (e.g. IRS-1 and CagA), oncogenic mutations (e.g. E76A) and allosteric inhibitors (e.g. SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.

5.
Med Oncol ; 38(5): 49, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33772655

RESUMO

Increasing evidence demonstrated that alternative splicing (AS) plays a vital role in tumorigenesis and clinical outcome of patient. However, systematical analysis of AS in lung squamous cell carcinoma (LUSC) is lacking and greatly necessary. Thus, this study was to systematically estimate the function of AS events served as prognostic indicators in LUSC. Among 31,345 mRNA AS events in 9633 genes, we detected 1996 AS in 1409 genes which have significant connection with overall survival (OS) of LUSC patients. Then, prognostic model based on seven types of AS events was established and we further constructed a combined prognostic model. The Kaplan-Meier curve results suggested that seven types of AS signatures and the combined prognostic model could exhibit robust performance in predicting prognosis. Patients in the high-risk group had significantly shorter OS than those in the low-risk group. The ROC showed all prognostic models had high accuracy and powerful predictive performance with different AUC ranging from 0.837 to 0.978. Moreover, the combined prognostic model had highest performance in risk stratification and predictive accuracy than single prognostic models and had higher accuracy than other mRNA model. Finally, a significant correlation network between survival-related AS genes and prognostic splicing factors (SFs) was established. In conclusion, our study provided several potential prognostic AS models and constructed splicing network between AS and SFs in LUSC, which could be used as potential indicators and treatment targets for LUSC patients.

6.
J Phys Chem Lett ; 12(12): 3151-3162, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33755493

RESUMO

Structure prediction is an important means to quickly understand new protein functions. However, the prediction of effects of proteins that have no detectable templates is still to be improved. Molecular dynamics simulation is supposed to be the primary research tool for structure predictions, but it still has limitations of huge computational cost in all-atom (AA) models and rough accuracy in coarse-grained (CG) models. We propose a universal multiscale simulation strategy named AIMS in which simulations can iteratively switch among multiple resolutions in order to adaptively trade off AA accuracy and CG high-efficiency. AIMS follows the idea of CG-guided enhanced sampling so that final results always keep AA accuracy. We successfully achieve four ab initio and four data-assisted protein structure predictions using AIMS. The prediction result is an ensemble rather than a structure and provides special insights on folding metastable states. AIMS is estimated to achieve a computational speed about 40 times faster than that of conventional AA simulations.

7.
Environ Pollut ; 279: 116931, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33756242

RESUMO

Stringent mitigation measures have reduced wintertime fine particulate matter (PM2.5) concentrations by 42.2% from 2013 to 2018 in the Beijing-Tianjin-Hebei (BTH) region, but severe PM pollution still frequently engulfs the region. The observed nitrate aerosols have not exhibited a significant decreasing trend and constituted a major fraction (about 20%) of the total PM2.5, although the surface-measured NO2 concentration has decreased by over 20%. The contributions of nitrogen oxides (NOX) emissions mitigation to the nitrate and PM2.5 concentrations and how to alleviate nitrate aerosols efficiently under the current situation still remains elusive. The WRF-Chem model simulations of a persistent and heavy PM pollution episode in January 2019 in the BTH reveal that NOX emissions mitigation does not help lower wintertime nitrate and PM2.5 concentrations under current conditions in the BTH. A 50% reduction in NOX emissions only decreases nitrate mass by 10.3% but increases PM2.5 concentrations by 3.2%, because the substantial O3 increase induced by NOX mitigation offsets the HNO3 loss and enhances sulfate and secondary organic aerosols formation. Our results are further consolidated by the occurrence of severe PM pollution in the BTH during the COVID-19 outbreak, with a significant reduction in NO2 concentration. Mitigation of NH3 emissions constitutes the priority measure to effectively lower the nitrate and PM2.5 concentrations in the BTH under current conditions, with 35.5% and 12.7% decrease, respectively, when NH3 emissions are reduced by 50%.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar/prevenção & controle , Pequim , China , Monitoramento Ambiental , Humanos , Material Particulado/análise
8.
ACS Synth Biol ; 10(3): 632-639, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33687200

RESUMO

Adipic acid is a versatile aliphatic dicarboxylic acid. It is applied mainly in the polymerization of nylon-6,6, which accounts for 50.8% of the global consumption market of adipic acid. The microbial production of adipic acid avoids the usage of petroleum resources and the emission of harmful nitrogen oxides that are generated by traditional chemical synthetic approaches. However, in the fermentation process, the low theoretical yield and the usage of expensive inducers hinders the large-scale industrial production of adipic acid. To overcome these challenges, we established an oxygen-dependent dynamic regulation (ODDR) system to control the expression of key genes (sucD, pyc, mdh, and frdABCD) that could be induced to enhance the metabolic flux of the reductive TCA pathway under anaerobic conditions. Coupling of the constitutively expressed adipic acid synthetic pathway not only avoids the use of inducers but also increases the theoretical yield by nearly 50%. After the gene combination and operon structure were optimized, the reaction catalyzed by frdABCD was found to be the rate-limiting step. Further optimizing the relative expression levels of sucD, pyc, and frdABCD improved the titer of adipic acid 41.62-fold compared to the control strain Mad1415, demonstrating the superior performance of our ODDR system.

9.
Food Chem ; 353: 129447, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33714122

RESUMO

In order to explore the correlation between the production of propionic acid (PA) and the succession of bacterial community during the fermentation of gray sufu, high-throughput sequencing and HPLC (High Performance Liquid Chromatography) were used to monitor the changes of bacterial community and metabolite content. The abundance and metabolite concentration of Propionibacterium increased rapidly in the early stage of fermentation. In the middle stage, the abundance of Lactobacillus began to increase, while the pH decreased rapidly. In the late stage, the concentration of PA began to decrease, but it remained at a high level at the end of fermentation. Correlation analysis showed that Lactobacillus and Bacillus had a strong negative correlation with PA and its precursor. The results showed that Fusobacterium, Providencia, Lactobacillus and Bacillus could be the key factors to reduce the PA content. This study provides a new idea for the quality control of traditional fermented food.

10.
Ann Palliat Med ; 10(3): 2766-2775, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33549014

RESUMO

BACKGROUND: Recently, several clinical studies have evaluated the first-line use of immune checkpoint inhibitors (ICIs) combined with platinum-doublet chemotherapy in patients with non-squamous non-small cell lung cancer (NSCLC), however, the differences in safety and efficacy between the various types of ICIs still require investigation. In this study, we evaluated the efficacy and safety of the first-line use of ICIs combined with platinum-doublet chemotherapy in patients with non-squamous NSCLC by meta-analysis and indirect comparison. METHODS: Literature searches were performed using PubMed, the Cochrane Library, Embase, China Knowledge Resource Integrated Database, and Wanfang Data to identify all relevant randomized clinical trials for non-squamous NSCLC after 2010. Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) were pooled for meta-analysis and indirect comparison. Subgroup analyses were conducted to examine the factors associated with PFS. RESULTS: The meta-analysis showed that the additional use of ICIs could significantly improve PFS and OS. The indirect comparison showed no significant difference in pembrolizumab + chemotherapy and atezolizumab + chemotherapy in the reducing of disease progression, while a significant difference in restricted mean survival time (RMST) was found between pembrolizumab + chemotherapy compared with atezolizumab + chemotherapy. A significant increase in grade ≥3 AEs was observed with the additional use of atezolizumab combined with chemotherapy. Subgroups including PD-1 status [high (>50%), intermediate (1-49%), and negative (<1%) expression], sex (male and female), smoking status (current or former smoker, and never smoked), liver metastases (with and without), age (>65 and ≤65) and Eastern Cooperative Oncology Group (ECOG) score (ECOG=0 and ECOG=1) were all associated with better PFS. CONCLUSIONS: This meta-analysis confirmed the treatment effects of ICIs combined with chemotherapy for non-squamous NSCLC. The pembrolizumab combination group had a greater RMST benefit compared with the atezolizumab combination group. Furthermore, our study also demonstrated a PFS advantage for non-squamous NSCLC using ICIs combined with chemotherapy irrespective of programmed death-ligand 1 (PD-L1) expression level, smoking status, liver metastasis status, sex, age and ECOG score. Due to the significant increase in AEs (> grade 3), more attention should be paid to the additional use of atezolizumab.

11.
Cereb Cortex ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33570093

RESUMO

Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.

12.
J Ethnopharmacol ; 273: 113950, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-33610713

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Thesium chinense Turcz. has been used to treat mastitis, pulmonitis, tonsillitis, iaryngopharyngitis and upper respiratory tract infections in the indigenous medicine of China for a long history. Presently, several pharmaceutics prepared by this medical herb have been clinically used for the therapy of infectious diseases. AIM OF THE REVIEW: This review aims to comprehensively summarize the current researches on the ethnomedical, phytochemical and pharmacological aspects of T. chinense, and discuss their possible opportunities for the future research. MATERIALS AND METHODS: Extensive database searches, including Web of Science, SciFinder, Google Scholar and China Knowledge Resource Integrated, were performed using keywords such as 'Thesium chinense', 'Bai Rui Cao', and their chemical constituents. In addition, local classic herbal literature on ethnopharmacology and relevant textbooks were consulted to provide a comprehensive survey of this ethnomedicine. RESULTS: Thirty four chemical constituents, including flavonoids, alkaloids, and terpenoids, have been identified from T. chinense. Of which, flavonoids are the predominant and characteristic constituents. The crude extracts, the purified constituents, and commercial available pharmaceutics have displayed diverse in vitro and in vivo pharmacological functions (e.g. anti-inflammation, antimicrobial activity, analgesic effect, hepaprotection), and are particularly useful as a potential therapeutic agent against inflammation-related diseases. CONCLUSIONS: T. chinense is an important ethnomedical medicine and possesses a satisfying effect for treating inflammation, microbial infection, and upper respiratory diseases. It has received plenty of researches on its phytochemical and pharmacological aspects since 1970s. These findings definitely establish the link between chemical composition and pharmacological application, and support the ethnomedical use of T. chinense in the indigenous medicine of China. However, chemical composition of this plant and the molecular mechanisms of purified constituents have not been comprehensively investigated, and thus the trace constituents and the therapeutic targets of bioactive constituents deserve a further exploration. Collectively, the researchers should pay more attention to a better understanding and application of this ethnomedical plant.

13.
Commun Biol ; 4(1): 226, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597714

RESUMO

NKCC and KCC transporters mediate coupled transport of Na++K++Cl- and K++Cl- across the plasma membrane, thus regulating cell Cl- concentration and cell volume and playing critical roles in transepithelial salt and water transport and in neuronal excitability. The function of these transporters has been intensively studied, but a mechanistic understanding has awaited structural studies of the transporters. Here, we present the cryo-electron microscopy (cryo-EM) structures of the two neuronal cation-chloride cotransporters human NKCC1 (SLC12A2) and mouse KCC2 (SLC12A5), along with computational analysis and functional characterization. These structures highlight essential residues in ion transport and allow us to propose mechanisms by which phosphorylation regulates transport activity.

14.
J Phys Chem Lett ; 12(9): 2232-2244, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33635675

RESUMO

Profound understanding of the luminescence mechanism and structure-property relationship is vital for Cu(I) thermally activated delayed fluorescence (TADF) emitters. Herein, we theoretically simulated luminescent behavior in both solution and solid phases for two Cu(I) complexes and found the following: (i) The strengthened spin-orbit coupling (SOC) effect by more dx2-y2 orbital contributions and well-restricted structural distortion via remarkable intramolecular interaction in [Cu(dmp)(POP)]+ enable the emission at room temperature to be a mixture of direct phosphorescence (10%) and TADF (90%). (ii) Benefiting from enhanced steric hindrance and the electron-donating ability of the paracyclophane group, the narrowed S1-T1 energy separation (ΔEST) in [Cu(dmp)(phanephos)]+ accelerates the reverse intersystem crossing, promoting the TADF rate (1.88 × 105 s-1) and intensity ratio (98.3%). These results indicate that the small ΔEST is superior for reducing the lifetime and that the strong SOC stimulates the phosphorescence to compete with TADF, which are both conducive to avoiding collision-induced exciton quenching and reducing the roll-off in devices.

15.
J Cell Biol ; 220(4)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33605979

RESUMO

Endocytosed proteins can be delivered to lysosomes for degradation or recycled to either the trans-Golgi network or the plasma membrane. It remains poorly understood how the recycling versus degradation of cargoes is determined. Here, we show that multiple extracellular stimuli, including starvation, LPS, IL-6, and EGF treatment, can strongly inhibit endocytic recycling of multiple cargoes through the activation of MAPK11/14. The stress-induced kinases in turn directly phosphorylate SNX27, a key regulator of endocytic recycling, at serine 51 (Ser51). Phosphorylation of SNX27 at Ser51 alters the conformation of its cargo-binding pocket and decreases the interaction between SNX27 and cargo proteins, thereby inhibiting endocytic recycling. Our study indicates that endocytic recycling is highly dynamic and can crosstalk with cellular stress-signaling pathways. Suppression of endocytic recycling and enhancement of receptor lysosomal degradation serve as new mechanisms for cells to cope with stress and save energy.

16.
Phys Chem Chem Phys ; 23(3): 2430-2437, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33459730

RESUMO

Intrinsically disordered proteins (IDPs) are a group of proteins that lack well-defined structures under native conditions and carry out crucial physiological functions in various biochemical pathways. Due to the heterogeneous nature of IDPs, molecular dynamics simulations have been extensively adopted to investigate the conformational ensembles and dynamic properties of these proteins. However, their accuracy remains limited by the development of force fields and sampling algorithms. Here, we evaluated the quality of both force fields and enhanced sampling algorithms based on five short pepX peptides. Our results show that the more extended conformational ensembles sampled by the AMOEBA polarizable force field present a higher ability to reproduce experimental NMR observables than AMBER and CHARMM classical force fields. Moreover, a better agreement with experiments is achieved in the simulation of IaMD (integrated accelerated molecular dynamics) than in aMD (accelerated molecular dynamics). The results together indicate that the combination of AMOEBA force field and IaMD enhanced sampling might be a better choice for simulating IDPs. This work may provide important clues for developments and applications of force fields and enhanced sampling methods in future simulations of IDPs.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Oligopeptídeos/química , Algoritmos , Bases de Dados de Compostos Químicos , Simulação de Dinâmica Molecular
18.
Diseases ; 9(1)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450825

RESUMO

Chemo and radiation therapies are the most commonly used therapies for cancer, but they can induce DNA damage, resulting in the apoptosis of host cells. DNA double-stranded breaks (DSBs) are the most lethal form of DNA damage in cells, which are constantly caused by a wide variety of genotoxic agents, both environmentally and endogenously. To maintain genomic integrity, eukaryotic organisms have developed a complex mechanism for the repair of DNA damage. Researches reported that many cellular long noncoding RNAs (lncRNAs) were involved in the response of DNA damage. The roles of lncRNAs in DNA damage response can be regulated by the dynamic modification of N6-adenosine methylation (m6A). The cellular accumulation of DNA damage can result in various diseases, including cancers. Additionally, lncRNAs also play roles in controlling the gene expression and regulation of autophagy, which are indirectly involved with individual development. The dysregulation of these functions can facilitate human tumorigenesis. In this review, we summarized the origin and overview function of lncRNAs and highlighted the roles of lncRNAs involved in the repair of DNA damage.

19.
Lung Cancer ; 152: 39-48, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33341538

RESUMO

OBJECTIVES: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20 ins) mutations are generally associated with de novo resistance to first- or second-generation EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). However, the real efficacy of osimertinib for this subset remains elusive. We performed this study to investigate the real efficacy of osimertinib for Chinese advanced NSCLC patients harboring EGFR ex20 ins mutations. MATERIALS AND METHODS: We retrospectively collected data of metastatic NSCLC patients with EGFR ex20 ins mutations who were treated with osimertinib 80 mg or 160 mg once daily in our center from June 2017 to May 2020. Progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were assessed. RESULTS: A total of 62 cases with EGFR ex20 ins mutations were included, and the major insertion variant was D770_N771insSVD and V769_D770insASV (45.1 %). Concurrent TP53 mutation was most commonly observed (59.7 %). Four patients showed partial response, 29 cases with stable disease and 29 showed progressive disease as best response to osimertinib (ORR: 6.5 %, DCR: 53.2 %). The median PFS (mPFS) in total patients was 2.3 (95 %CI, 1.5-3.1) months. Patients harboring A763_Y764insFQEA/D770delinsGY variants showed numerically longer mPFS than those with other variants (4.2 vs. 2.2 months, P =  0.164). Patients who failed to osimertinib and occurred extracranial progression showed similar mPFS to those with intracranial progression (2.3 vs. 1.9 months, P =  0.142). Median PFS was not significantly different between patients who received osimertinib 80mg or 160mg once daily (2.5 vs. 1.3 months, P = 0.161), either with no significance when it used in fist-line setteing or bove (3.0 vs. 2.2 months, P =  0.639). CONCLUSION: The unique insertion variant A763_Y764insFQEA and D770delinsGY might better respond to osimertinib than other ex20 ins subtypes. Osimertinib either 80 mg or 160 mg once daily showed less activity in Chinese NSCLC patients harboring diverse EGFR ex20 ins mutations.

20.
Ann Palliat Med ; 10(1): 285-291, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33353353

RESUMO

BACKGROUND: To investigate the reference value of blood gas analysis and related factors in healthy adults in Diqing Tibetan Autonomous Prefecture in Yunnan Province. METHODS: From August 24, 2018 to August 11, 2020, healthy people between the ages of 18 and 70 years were observed at the Physical Examination Center of People's Hospital of Diqing Tibetan Autonomous Prefecture in Yunnan province. Participant information and clinical characteristics were collected. Blood gas analyzer was used to measure PH value, arterial partial oxygen pressure (PaO2), arterial partial pressure of carbon dioxide (PaCO2), arterial oxygen saturation (SaO2), acidity (pH), actual bicarbonate (AB) and residual base (BE). The participants' basic and blood gas indicator data were analyzed, and the blood gas reference values and related factors were analyzed using chi-squared tests, Mann-Whitney-Wilcoxon Test, and Spearman's correlation analysis. RESULTS: A total of 1,218 eligible health examination participants were included. They had an average age of 40 [31-47] years, and males accounted for 51.0%. In terms of blood gas reference values, the average pH value was moderate, and the values of PaO2, SaO2, PaCO2, AB, and BE were low. PaO2 was basically matched with the estimated value of the domestic model formula. These indexes were found to be correlated with social demographic characteristics such as sex, age, and smoking history. CONCLUSIONS: The correlations between the indexes and social demographic characteristics may be helpful in the prediction of blood gas analysis results in clinical practice. For men, middle-aged and elderly people, or adults with a history of active smoking/biofuel exposure, blood gas PaO2 and PaCO2 should be monitored to facilitate the early intervention of respiratory failure. The PaO2 data basically matched the estimated values of the domestic model formula, suggesting that other regions in the Prefecture could use comprehensive epidemiological data and model methods to guide clinical work.

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