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1.
J Inflamm Res ; 15: 2775-2787, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35518839

RESUMO

Objective: To investigate the clinicopathological features, and mutations of NRAS, KRAS, BRAF and MAP2K1 genes in extranodal Rosai-Dorfman disease (RDD). Methods: The clinic opathological features of 27 patients with extranodal RDD were retrospectively analyzed, and the NRAS, KRAS, BRAF and MAP2K1 genes mutation were detected by Sanger sequencing. Results: The male to female ratio was 1.7:1. The average age was 46.9 years. There were skin lesions in 12 cases (44.4%) and head and neck lesions in 8 cases (29.6%). Microscopically, those patients with skin RDD had lesions characterized by clear and dark intervals and obvious emperipolesis, while in other parts, the background was more complex. About 21.1% (4/19) had mutations, including 3 mutations in NRAS 2 exon and 1 mutation in KRAS 2 exon. Two of the three NRAS mutations were located in the skin, accounting for 20% (2/10) of skin RDD. Conclusion: Extranodal RDD was more common in males than in females, and might occur in all ages, with a greater incidence in skin, head, and neck. Besides the obvious microscopic characteristics in those with skin RDD, the background of other parts was complex and easily missed or misdiagnosed. Some RDD with gene mutations, mainly in NRAS 2 exon, especially in skin RDD, support partial RDD is a clonal disease.

2.
Cell ; 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35512704

RESUMO

Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

3.
Carbohydr Polym ; 289: 119434, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35483847

RESUMO

Drying-induced hornification is an inevitable phenomenon of cellulosic fibers, which is used to describe internal aggregation structure changes of cellulosic fibers upon drying or water removal. To investigate the hornification process, never-dried cellulosic fibers with different components were thermally dried to different moisture contents. The results indicated that the hornification process could be divided into four stages, including the first crystallization period (>70% moisture), the cocrystallization period (70-31% moisture), the hemicellulose control period (31-11% moisture), and the second crystallization period (11-0% moisture). The decrease of water retention value (WRV) occurred in the cocrystallization period and the second crystallization period, which meant hornification happened in these two periods. Besides, hemicellulose and lignin inhibited hornification by reducing cellulose cocrystallization. The work elucidates the hornification process and mechanism of cellulosic fibers,which will be helpful to control the properties of cellulosic materials for extended utilization.


Assuntos
Celulose , Dessecação , Celulose/química , Cristalização , Lignina , Água/química
4.
STAR Protoc ; 3(2): 101325, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35479113

RESUMO

RNA transcripts can anneal with template DNA strands to form RNA-DNA hybrids (or R-loops if the non-template DNA strands exist), which play a variety of roles in many physiological processes. Here, we provide an accessible and reproducible approach for immunofluorescent staining of RNA-DNA hybrids with the S9.6 antibody in spread meiotic nuclei of Saccharomyces cerevisiae. This protocol allows the examination of RNA-DNA hybrids as clearly distinguishable foci and the colocalizations of RNA-DNA hybrids with other proteins. For complete details on the use and execution of this protocol, please refer to Yang et al. (2021).


Assuntos
RNA , Saccharomyces cerevisiae , DNA/genética , RNA/genética , Saccharomyces cerevisiae/genética
5.
Proc Natl Acad Sci U S A ; 119(17): e2106902119, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35439061

RESUMO

SignificanceMeiotic crossover recombination is required for faithful chromosome segregation and promotes genetic diversity by reshuffling alleles between parental chromosomes. Meiotic chromosomes are organized into arrays of loops that are anchored to the proteinaceous axes. The length of the meiotic chromosome axis is intimately associated with crossover frequencies in yeast and higher eukaryotes. However, how chromosome axis length is regulated in meiosis is unknown. Here, we demonstrate that cohesin regulator Pds5 interacts with proteasomes to regulate meiotic chromosome axis length by modulating ubiquitination. This regulatory mechanism also includes two ubiquitin E3 ligases, SCF (Skp-Cullin-F-box) and Ufd4. These findings identify a molecular pathway in regulating chromosome organization and reveal an unexpected function of the ubiquitin-proteasome system in meiosis.


Assuntos
Complexo de Endopeptidases do Proteassoma , Ubiquitina , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Segregação de Cromossomos , Cromossomos/metabolismo , Meiose/genética , Complexo de Endopeptidases do Proteassoma/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Ubiquitina/genética
6.
J Environ Manage ; 311: 114847, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35272159

RESUMO

Coal-fired heating in winter is a primary source of air pollution in many countries. In northern China, the use of scattered coal for winter heating has led to severe environmental issues. In this study, we use a quasi-natural experiment in Shandong Province, China, to investigate the effectiveness of a cleaner heating transition policy. Specifically, we use a difference-in-differences approach to identify the effects of the cleaner heating transition policy on air pollution using high-resolution hourly data. Our findings indicate that implementation of the policy could effectively reduce air pollution by decreasing a PM2.5 by 7.32%, PM10 by 2.62%, SO2 by 3.98%, and NO2 by 4.67%. In addition, we used event study and a series of robustness checks to further support our findings. Notably, our findings indicate that implementation of the policy includes a spatial spillover effect, which differs according to the level of compulsory implementation and the distance to a city centre. Overall, our findings can help promote the application of a cleaner transitioning policy for the entire country and offer guidance for further policy development regarding the effective reduction of winter air pollution in the developing world.

7.
Nat Commun ; 13(1): 1291, 2022 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-35277510

RESUMO

Circadian humidity fluctuation is an important factor that affects human life all over the world. Here we show that spherical cap-shaped ionic liquid drops sitting on nanowire array are able to continuously output electricity when exposed to outdoor air, which we attribute to the daily humidity fluctuation induced directional capillary flow. Specifically, ionic liquid drops could absorb/desorb water around the liquid/vapor interface and swell/shrink depending on air humidity fluctuation. While pinning of the drop by nanowire array suppresses advancing/receding of triple-phase contact line. To maintain the surface tension-regulated spherical cap profile, inward/outward flow arises for removing excess fluid from the edge or filling the perimeter with fluid from center. This moisture absorption/desorption-caused capillary flow is confirmed by in-situ microscope imaging. We conduct further research to reveal how environmental humidity affects flow rate and power generation performance. To further illustrate feasibility of our strategy, we combine the generators to light up a red diode and LCD screen. All these results present the great potential of tiny humidity fluctuation as an easily accessible anytime-and-anywhere small-scale green energy resource.


Assuntos
Energia Renovável , Água , Eletricidade , Humanos , Umidade , Tensão Superficial
8.
Acta Radiol ; : 2841851221088917, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35345899

RESUMO

BACKGROUND: Intracranial atherosclerotic stenosis is a major cause of ischemic stroke, accounting for 30% of ischemic strokes in Asian populations. PURPOSE: To investigate the relationship between the degree of arterial stenosis and enhancement grade of intracranial atherosclerotic disease (ICAD), the plaque characteristics in different remodeling patterns, and its potential impact. MATERIAL AND METHODS: A total of 210 patients diagnosed with ICAD were enrolled in this retrospective study. Patients were divided into the middle cerebral artery (MCA) group (101 cases), posterior cerebral artery (PCA) group (14 cases), basilar artery (BA) group (71 cases), and intracranial segment of vertebral artery (VA) group (90 cases) according to the difference of diseased vessels. Data on presence or absence of ischemic infarction, intracranial vascular position of lesions, plaque characteristics, ICAD enhancement grade, remodeling index, and degree of arterial stenosis were collected for analysis. RESULTS: The incidence of ischemic infarction in enhancement grade 2 was significantly higher than that in enhancement grade 1 in MCA group (P = 0.019). Enhancement grade 2 of ICAD was an independent risk factor for the development of ischemic infarction (odds ratio = 4.60; 95% confidence interval: 1.91-11.03; P = 0.001). There was no significant statistical difference in infarct rate between different remodeling modalities (P>0.05). CONCLUSION: Enhancement grade of ICAD is significantly associated with the degree of stenosis and the occurrence of ischemic stroke, which varies in different intracranial vessels. The pattern of vascular remodeling varies among different intracranial vessels, and the pattern of vascular remodeling has a significant impact on plaque characteristics.

9.
Materials (Basel) ; 15(5)2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35269032

RESUMO

A non-equiatomic AlCoCr0.75Cu0.5FeNi alloy has been identified as a potential high strength alloy, whose microstructure and consequently properties can be widely varied. In this research, the phase structure, hardness, and magnetic properties of AlCoCr0.75Cu0.5FeNi alloy fabricated by laser powder bed fusion (LPBF) are investigated. The results demonstrate that laser power, scanning speed, and volumetric energy density (VED) contribute to different aspects in the formation of microstructure thus introducing alterations in the properties. Despite the different input parameters studied, all the as-built specimens exhibit the body-centered cubic (BCC) phase structure, with the homogeneous elemental distribution at the micron scale. A microhardness of up to 604.6 ± 6.8 HV0.05 is achieved owing to the rapidly solidified microstructure. Soft magnetic behavior is determined in all as-printed samples. The saturation magnetization (Ms) is dependent on the degree of spinodal decomposition, i.e., the higher degree of decomposition into A2 and B2 structure results in a larger Ms. The results introduce the possibility to control the degree of spinodal decomposition and thus the degree of magnetization by altering the input parameters of the LPBF process. The disclosed application potentiality of LPBF could benefit the development of new functional materials.

10.
Am J Cancer Res ; 12(2): 861-872, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35261808

RESUMO

Metabolic reprogramming, as a key hallmark of cancers, leads to the malignant behavior of pancreatic cancer, which is closely related to tumor development and progression, as well as the supportive tumor microenvironments. Although cells produce adenosine triphosphate (ATP) from glucose by glycolysis when lacking oxygen, pancreatic cancer cells elicit metabolic conversion from oxide phosphorylation to glycolysis, which is well-known as "Warburg effect". Glycolysis is critical for cancer cells to maintain their robust biosynthesis and energy requirement, and it could promote tumor initiation, invasion, angiogenesis, and metastasis to distant organs. Multiple pathways are involved in the alternation of glycolysis for pancreatic cancer cells, including UHRF1/SIRT4 axis, PRMT5/FBW7/cMyc axis, JWA/AMPK/FOXO3a/FAK axis, KRAS/TP53/TIGAR axis, etc. These signaling pathways play an important role in glycolysis and are potential targets for the treatment of pancreatic cancer. Mutations in glycolytic enzymes (such as LDH, PKM2, and PGK1) also contribute to the early diagnosis and monitoring of pancreatic cancer. In this review, we summarized the recent advances on the mechanisms for glycolysis in pancreatic cancer and the function of glycolysis in the progression of pancreatic cancer, which suggested new targets for cancer diagnosis and treatment.

11.
Org Lett ; 24(10): 1883-1888, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35266389

RESUMO

A facile synthetic method for 4-aryl-4,5-dihydropyrrole-3-carboxylates is developed, with a rhodium-catalyzed ring expansion strategy from readily available 2-(azetidin-3-ylidene) acetates and aryl boronic acids. Mechanistic investigations suggest a novel domino "conjugate addition/N-directed α-C(sp3)-H activation" process. The asymmetric catalytic synthesis of the 4-aryl-4,5-dihydropyrrole-3-carboxylate is realized by using QuinoxP* (91-97% ee). The synthetic utility of this protocol is demonstrated by the synthesis of 3,4-disubstituted or 2,3,4-trisubstituted pyrrolidines with excellent diastereoselectivities.


Assuntos
Azetidinas , Ródio , Acetatos , Ácidos Borônicos , Catálise
12.
J Hepatol ; 2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35219791

RESUMO

BACKGROUND & AIMS: Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance mechanism of HCC against this therapy is urgently needed. METHODS: We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64. RESULTS: We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transforms macrophages to the M2 phenotype to drive immune escape and anti-PD1 tolerance. Notably, Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, reset the tumor microenvironment and restore sensitivity to anti-PD1 by blocking the PKCα/ZFP64/CSF1 axis. CONCLUSIONS: We propose that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. Inhibiting this axis with Gö6976 or lenvatinib overcomes anti-PD1 resistance in HCC. LAY SUMMARY: Despite remarkable treatment progress, most patients with hepatocellular carcinoma respond poorly to anti-PD1 therapy (a type of immunotherapy). A deeper insight into the tolerance mechanisms to this therapy is urgently needed. Herein, we unravel a previously unexplored mechanism linking tumor progression, macrophage polarization, and anti-PD1 resistance, and offer an attractive novel target for anti-PD1 combination therapy, which may benefit patients with hepatocellular carcinoma.

13.
Sci Total Environ ; 824: 153976, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35181370

RESUMO

Plastic-shed vegetable production in China creates hotspots for emission of the potent greenhouse gas nitrous oxide (N2O) and the atmospheric pollutant nitric oxide (NO). To mitigate N2O and NO emissions, determination of the predominant processes of N2O and NO generation in plastic-shed vegetable production is important. Here, we reported the findings of a 2-year experimental study on the effects of reduced fertilization and/or drip irrigation on N2O and NO emissions during plastic-shed tomato production in northern China. Five treatments were applied: 1) over fertilization and flood irrigation (conventional practice); 2) fertilization reduced by 20% and flood irrigation; 3) fertilization reduced by 20% and drip irrigation; 4) fertilization reduced by 30% and drip irrigation, and 5) control (no fertilizer input and flood irrigation). Reduced both basal and top-dressed fertilization maintained tomato yields. Compared with conventional practices (mean annual N2O and NO emissions: 18.1 ± 1.3 and 0.79 ± 0.02 kg N ha-1 yr -1, respectively), fertilization reduction by 20%-30% decreased the annual N2O emission by 21.2%-27.0% owing to lower soil inorganic nitrogen (SIN) contents under the reduced fertilization practices. Switching from flood to drip irrigation might weaken denitrification due to lower soil moisture and less wet soil area, but increased SIN contents, and thus had no significant impact on annual N2O and NO emissions. Peak N2O fluxes occurred at soil temperature 28 °C and water-filled pore space (WFPS) > 60%, were higher than those for NO, and peak NO fluxes appeared 4-6 days later than N2O fluxes, consistent with the decline in WFPS. These observations indicated that N2O and NO from alkaline plastic-shed soil may be mainly generated via heterotrophic denitrification and nitrification, respectively. Reduced fertilization and drip irrigation in plastic-shed tomato production maintained crop productivity and mitigated N2O emission. These results could be integrated into the decision-making in sustainable plastic-shed production.


Assuntos
Lycopersicon esculentum , Verduras , Agricultura , China , Fertilização , Fertilizantes/análise , Óxido Nítrico , Nitrogênio , Óxido Nitroso/análise , Plásticos , Solo , Água
14.
Artigo em Inglês | MEDLINE | ID: mdl-35198031

RESUMO

BACKGROUND: Although the Bushen Huoxue (BSHX) recipe is commonly used for the effective treatment of the prethrombotic state of recurrent abortions, its mechanism of action is unclear. In this article, we investigated the therapeutic effects of BSHX on anti-cardiolipin antibody (ACA) positive recurrent miscarriage mice and the molecular mechanism involved in the treatment of the prethrombotic state of ACA-positive recurrent miscarriages based on the PI3K-Akt signaling pathway, to provide a scientific basis for clinical practice. METHODS: An ACA-positive recurrent miscarriage mouse model and normal pregnancy mouse model were adopted in this experiment. Seventy CBA/J female mice were induced to establish the ACA-positive recurrent model; the mice were mated with DBA/2 male mice. Of these mice, 50 became pregnant, which were randomly divided into a BSHX high-dose group (BH, 2.52 g/kg), BSHX medium-dose group (BM, 1.26 g/kg), BSHX low-dose group (BL, 0.63 g/kg), model group (M, distilled water), and an aspirin enteric-coated tablet group; each group had 10 mice. In addition, 16 CBA/J female mice were induced to establish the normal pregnant mouse model; the mice were mated with BALB/C male mice. Of these mice, 10 became pregnant, which were used as the blank control group (C) and received distilled water by gavage. Stillbirth and abortion rates were recorded for each group, and the uterine tissue, urine, and serum were collected. The serum expression levels of ACA, interleukin-6 (IL-6), progesterone ,estradiol, and endometrial histological changes were compared between the groups. Metabolomics was performed on the urine and uterine tissues of both groups using UHPLC-QTOF/MS, and the expression levels of PI3K, p-PI3K, AKT, and p-AKT proteins in the uterine tissues were detected using Western blot. RESULTS: Compared with the model pregnancy group, the BSHX high-dose group, BSHX medium-dose group, and BSHX low-dose group all had a lower absorption rate of mouse embryos, improved uterine histopathological morphology, significantly reduced serum levels of ACA and IL-6, increased serum levels of progesterone and estradiol, and significantly upregulated uterine levels of p-AKT, PI3K, and p-PI3K proteins. The metabolomic results showed that the metabolic levels in the urine and uterine tissues were significantly altered in the mouse model of ACA-positive recurrent abortion. The results also suggested that the pathogenesis of ACA-positive recurrent abortion may be associated with metabolic pathways, such as pentose, glucuronide, lysine degradation, and steroid hormone biosynthesis. CONCLUSION: The BSHX recipe improved the uterine histopathological morphology of pregnant mice and promoted vascular formation in uterine tissues. The mechanisms involved the reduction in serum ACA and IL-6 levels, the increment in serumprogesterone and estradiol levels, the upregulation of the levels of p-AKT, PI3K, and p-PI3K proteins, and the activation of the PI3K-Akt signaling pathway. These data will be useful for effective drug research and development.

15.
Bioengineered ; 13(3): 5868-5879, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35220891

RESUMO

This study aimed to compare the application value of capillary electrophoresis and next-generation sequencing for immunoglobulin (IG) gene rearrangement in the diagnosis of classic Hodgkin's lymphoma. Twenty paraffin-embedded specimens from patients with classic Hodgkin's lymphoma were screened. For gene rearrangement detection, the ABI 3500 Genetic Analyzer and ABI Ion GeneStudio S5 Plus sequencing system were used, respectively, and the results were compared. Five cases with monoclonal rearrangements (25%, 5/20) were detected by Capillary Electrophoresis, and positivity for the FR1, FR2, FR3, and IGк loci was 5%, 10%, 10%, and 15%, respectively; 12 cases with monoclonal rearrangements (60%, 12/20) were detected by Next-generation Sequencing where the positivity of the above corresponding loci were 35%, 45%, 50%, and 30%, respectively. Among the 20 samples, 6 IGк clonal rearrangements were detected, and the usage frequency (66.7%) of IGкJ4 was the highest in the IGкJ subgroup. The usage frequency of IGкV1 and IGкV3 in the GкV sub-group was 33.3% and 33.3%, respectively. Twelve immunoglobulin heavy chain (IGH) clonal rearrangements were detected among the 20 samples, and the order of usage frequency in the IGH joining region J (IGHJ) subgroup was IGHJ4 > IGHJ5 > IGHJ6 > IGHJ3. The gene with the highest usage frequency in the IGH variable (IGHV) subgroup was IGHV3 (50%) and the percentage of IGHV mutations ranged from 0% ± 11.45% with an average frequency of 3.34%. Compared with Capillary Electrophoresis, Next-generation Sequencing showed a higher positivity in the detection of gene clonal rearrangements, was more accurate in the interpretation of results.


Assuntos
Doença de Hodgkin , Cadeias Pesadas de Imunoglobulinas , Eletroforese Capilar , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética
16.
Artigo em Inglês | MEDLINE | ID: mdl-35073271

RESUMO

Cardiovascular diseases (CVDs) are the leading cause of death, affecting the cardiac dynamics over the cardiac cycle. Estimation of cardiac motion plays an essential role in many medical clinical tasks. This article proposes a probabilistic framework for image registration using compact support radial basis functions (CSRBFs) to estimate cardiac motion. A variational inference-based generative model with convolutional neural networks (CNNs) is proposed to learn the probabilistic coefficients of CSRBFs used in image deformation. We designed two networks to estimate the deformation coefficients of CSRBFs: the first one solves the spatial transformation using given control points, and the second one models the transformation using drifting control points. The given-point-based network estimates the probabilistic coefficients of control points. In contrast, the drifting-point-based model predicts the probabilistic coefficients and spatial distribution of control points simultaneously. To regularize these coefficients, we derive the bending energy (BE) in the variational bound by defining the covariance of coefficients. The proposed framework has been evaluated on the cardiac motion estimation and the calculation of the myocardial strain. In the experiments, 1409 slice pairs of end-diastolic (ED) and end-systolic (ES) phase in 4-D cardiac magnetic resonance (MR) images selected from three public datasets are employed to evaluate our networks. The experimental results show that our framework outperforms the state-of-the-art registration methods concerning the deformation smoothness and registration accuracy.

17.
bioRxiv ; 2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35018375

RESUMO

Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human and murine ß-coronaviruses. The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in ß-coronavirus replication. Spike protein uptake was blocked by CSNK2A inhibition, indicating that antiviral activity was due in part to a suppression of viral entry. CSNK2A inhibition may be a viable target for development of new broad spectrum anti-ß-coronavirus drugs.

18.
Nanotechnology ; 33(19)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35086083

RESUMO

Quantum dot (QD) features many exceptional optical performances but is also vulnerable to moisture which results in structural damage and luminescent decrease. This work provided and fabricated a novel superior hydrophobic methylated core/shell silica-coated QD (MSQ) for high water stability. QD was coated with a silica shell and then surface-methylated by trimethyl silane. Mercaptopropyl trimethoxy silane, tetraethyl orthosilicate, and ethoxy trimethyl silane were utilized as the ligand exchanger, the raw material of silica, and the surface modification, respectively. Characterization results illustrated the core/shell structure of MSQ. In addition, its water contact angle was up to 159.6°. QD-, silica-coated QD(SQ)-, and MSQ-silicone were made and displayed similar absorption, emission, and excitation spectra but different water stabilities. The photoluminescence intensity and photoluminescence quantum yield of MSQ-silicone hardly changed during 15 d of water immersion, in contrast to the dramatical decrease of other two kinds of composite silicone. Specifically, the photoluminescence quantum yield decreases of MSQ-, SQ-, and QD-silicone were 1%, 40%, and 43%, respectively. Therefore, MSQ had a much better water stability. The superior hydrophobic methylated silica-coated QD has a great potential to realize the long-term working stability in a humid environment and the wider application in diverse fields.

19.
Environ Sci Pollut Res Int ; 29(12): 16817-16829, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34997929

RESUMO

Dissolved organic matter (DOM) and microbes are key in the planetary carbon cycle, and research on them can lead to a better understanding of the global carbon cycle and an improved ability to cope with environmental challenges. Several papers have reviewed one or several aspects of the interaction of DOM and microbes, but no overall review has been performed. Here, we bibliometrically analyzed all publications from the Web of Science on DOM and microbes (1991-2020). The results showed that studies on DOM and microbes grew exponentially during this period; the USA contributed the most to the total publications, and China has had the fastest increasing rate since 2010. Moreover, we used the Latent Dirichlet Allocation model to identify topics and determine their (cold or hot) trends by analyzing the abstracts of 9851 publications related to DOM and microbes. A total of 96 topics were extracted, and these topics that are related to the source, composition, and removal path of DOM and the temporal-spatial patterns of DOM and microbes consistently rose from 1991 to 2020. Most studies have used accurate and rapid methods combined with microbiological genetic approaches to study the interaction of DOM and microbes in terrestrial and aquatic ecosystems. The results also showed that the impacts of climate change and land use on the interaction of DOM and microbes, and topics related to human health have received considerable attention. In the future, the interaction mechanism of DOM and microbes and its response to environmental change should be further elucidated.


Assuntos
Ecossistema , Rios , Bibliometria , Mudança Climática , Humanos
20.
Cells ; 11(2)2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35053380

RESUMO

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that is activated by a variety of endogenous metabolites or xenobiotics. Its downstream target genes are involved in metabolism, inflammation and processes closely related to cancer. However, the stability regulation of PXR protein resulting from post-translational modification is still largely undefined. In the present study, primary mouse hepatocytes, hepatoma HepG2 cells and HEK 293T cells were used to investigate gene expression and protein interactions. The role of kinases was evaluated by RNA interference and overexpression constructs with or without PXR phosphorylation site mutations. The activity of CYP3A4 and P-gp was determined by enzymatic and substrate accumulation assays. It was found that E3 ubiquitin ligase TRIM21 mediates the ubiquitination and degradation of PXR and plays an important role in regulating the activity of PXR. On this basis, PXR phosphorylation-associated kinases were evaluated regarding regulation of the stability of PXR. We found cyclin dependent kinase 2 (CDK2) exclusively phosphorylates PXR at Ser350, promotes its disassociation with Hsp90/DNAJC7, and leads to subsequent TRIM21-mediated PXR ubiquitination and degradation. As well-known CDK inhibitors, dinaciclib and kenpaullone stabilize PXR and result in elevated expression and activity of PXR-targeted DMETs, including carboxylesterases, CYP3A4 and P-gp. The suppressed degradation of PXR by CDK2 inhibitors denotes dinaciclib-induced promotion of PXR-targeted genes. The findings of CDK2-mediated PXR degradation indicate a wide range of potential drug-drug interactions during clinical cancer therapy using CDK inhibitors and imply an alternative direction for the development of novel PXR antagonists.


Assuntos
Quinase 2 Dependente de Ciclina/metabolismo , Receptor de Pregnano X/metabolismo , Proteólise , Ribonucleoproteínas/metabolismo , Transdução de Sinais , Ubiquitinação , Óxidos N-Cíclicos/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Indolizinas/farmacologia , Chaperonas Moleculares/metabolismo , Fosforilação , Fosfosserina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Compostos de Piridínio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos
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