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1.
Macromol Rapid Commun ; : e1900570, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31894599

RESUMO

Covalent organic frameworks (COFs) as drug delivery systems have shown great promise, but their pharmaceutical applications are often limited by complex building blocks, tedious preparations, irregular shape, and uncontrolled drug release within target cells. Herein, a facile strategy is developed to prepare PEGylated redox-responsive nanoscale COFs (denoted F68@SS-COFs) for efficiently loading and delivering doxorubicin (DOX) by use of FDA-approved Pluronic F68 and commercially available building blocks. The obtained F68@SS-COFs with controlled size, high stability, and good biocompatibility can not only achieve a very high DOX-loading content (about 21%) and very low premature leakage at physiological condition but can also rapidly respond to the tumor intracellular microenvironment and efficiently release DOX to kill tumor cells. Considering the readily available raw materials, simple preparation process, and desirable redox-responsiveness, the strategy provided here opens up a promising avenue to develop well-defined COFs-based nanomedicines for cancer therapy.

2.
J Environ Sci (China) ; 88: 273-282, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31862068

RESUMO

The effects of disinfection efficiency on microbial communities and the corrosion of cast iron pipes in drinking water distribution systems (DWDSs) were studied. Two annular reactors (ARs) that simulated actual running conditions with UV/Cl2 disinfection and chlorination alone were used. High chlorine consumption and corrosion rate were found in the AR with UV/Cl2. According to functional genes and pyrosequencing tests, a high percentage of iron recycling bacteria was detected within the biofilm of the AR with Cl2 at early running stage, whereas siderophore-producing bacteria were dominant in the biofilm of the AR with UV/Cl2. At the early running stage, the sequential use of UV light and an initial high chlorine dosage suppressed the biomass and iron-recycling bacteria in both bulk water and biofilms, thereby forming less protective scales against further corrosion, which enhanced chlorine consumption. Non-metric multidimensional scaling analysis showed that the bacterial communities in the ARs shaped from within rather than being imported by influents. These results indicate that the initial high disinfection efficiency within the distribution system had not contributed to the accumulation of iron-recycling bacteria at the early running stages. This study offer certain implications for controlling corrosion and water quality in DWDSs.

3.
Gut ; 69(1): 18-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171626

RESUMO

OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-ß as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.


Assuntos
Adenocarcinoma/secundário , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Instabilidade Cromossômica , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/imunologia , Ploidias , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Sequenciamento Completo do Exoma/métodos
4.
Oncogene ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831835

RESUMO

The original version of this Article omitted the following from the Acknowledgements: Professor Stebbing sits on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare. This has now been corrected in both the PDF and HTML versions of the Article.

5.
Bioresour Technol ; : 122459, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31784252

RESUMO

Stable sewage nitrogen removal with nitrogen removal efficiency of 87.5 ± 2.2% was achieved in a partial nitrification-anammox (PNA) biofilm system at low temperatures (12.8-16.3 °C). High-throughput sequencing analysis indicated that the microbial community structure in the sequencing batch biofilm reactor (SBBR) remained reasonably stable. Candidatus Brocadia was the only detected anammox genus and remained stable at 0.3-0.5%. Some psychrotolerant microorganisms that could secrete cryoprotective extracellular polymeric substances (EPS), including Flavobacterium and Thermomonas, were enriched at low temperatures. This could be conducive to the stable operation of the PNA-SBBR. Moreover, according to the EPS composition and characteristics analysis, the secretion of tightly-bound EPS that bound to the cell surface containing plentiful protein was stimulated at low temperatures, further improving the system stability. Overall, the reasonably stable microbial community structure, enrichment of psychrotolerant microorganisms, and increased secretion of EPS could play important roles for stable sewage nitrogen removal at low temperatures.

6.
Sci Adv ; 5(11): eaax8849, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31799396

RESUMO

Exosome cargoes are highly varied and include proteins, small RNAs, and genomic DNA (gDNA). The presence of gDNA suggests that different intracellular compartments contribute to exosome loading, resulting in distinct exosome subpopulations. However, the loading of gDNA and other nuclear contents into exosomes (nExo) remains poorly understood. Here, we identify the relationship between cancer cell micronuclei (MN), which are markers of genomic instability, and nExo formation. Imaging flow cytometry analyses reveal that 10% of exosomes derived from cancer cells and <1% of exosomes derived from blood and ascites from patients with ovarian cancer carry nuclear contents. Treatment with genotoxic drugs resulted in increased MN and nExos both in vitro and in vivo. We observed that multivesicular body precursors and exosomal markers, such as the tetraspanins, directly interact with MN. Collectively, this work provides new insights related to nExos, which have implications for cancer biomarker development.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31802657

RESUMO

A novel drug-delivery nanosystem based on near-infrared (NIR) light-degradable antimony nanoparticles (AMNP) have been developed for synergistic chemo-phototherapy in vitro. The monodispersed AMNP were synthesized by using a simple and cost-effective method. Positively charged doxorubicin hydrochloride (DOX) was loaded onto the negatively charged surface of AMNP via electrostatic interaction and finally modified by polyacrylic acid (PAA) to enhance biocompatibility. Under NIR (808 nm) laser irradiation of the AMNP-DOX-PAA nanosystem, not only was high photothermal conversion efficiency of AMNP achieved but also pH-dependent DOX release was enhanced due to laser-induced hyperthermia. As a consequence, almost all of the HeLa cells (around 97%) were killed because of the combined effects of chemotherapy and photothermal therapy. More interestingly, AMNP showed very fast (about 10 min) laser-induced degradation that may help to minimize long-term toxicity after therapy by using same-wavelength NIR laser irradiation (808 nm). Computational total energy calculations and molecular dynamics simulations based on density functional theory (DFT) suggest that the NIR laser irradiation induces a photothermally activated reaction on the surface of AMNP in water, which can lead to surface degradation via the formation of Sb-H bonds first and then Sb-OH bonds upon further increase of temperature. This work demonstrates a simple platform that has potential applications for synergistic and highly effective chemo-photothermal therapy based on photodegradable nanoparticles.

8.
Biol Chem ; 401(1): 3-29, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31815377

RESUMO

It is now becoming clear that human metabolism is extremely plastic and varies substantially between healthy individuals. Understanding the biochemistry that underlies this physiology will enable personalized clinical interventions related to metabolism. Mitochondrial quality control and the detailed mechanisms of mitochondrial energy generation are central to understanding susceptibility to pathologies associated with aging including cancer, cardiac and neurodegenerative diseases. A precision medicine approach is also needed to evaluate the impact of exercise or caloric restriction on health. In this review, we discuss how technical advances in assessing mitochondrial genetics, cellular bioenergetics and metabolomics offer new insights into developing metabolism-based clinical tests and metabolotherapies. We discuss informatics approaches, which can define the bioenergetic-metabolite interactome and how this can help define healthy energetics. We propose that a personalized medicine approach that integrates metabolism and bioenergetics with physiologic parameters is central for understanding the pathophysiology of diseases with a metabolic etiology. New approaches that measure energetics and metabolomics from cells isolated from human blood or tissues can be of diagnostic and prognostic value to precision medicine. This is particularly significant with the development of new metabolotherapies, such as mitochondrial transplantation, which could help treat complex metabolic diseases.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31815416

RESUMO

Brain-like neuromorphic computing system provides an alternative approach for the future computer for its characteristic of high-efficiency, power-efficient, self-learning and parallel computing. Therefore, the imitation of synapse behavior based on microelectronics is particularly important. Recently, the synaptic transistors have received widespread attention. Among them, solid oxide-based synaptic transistors are more compatible with the large-scale fabrication than the liquid and organic-based transistors. So the development of oxide synaptic transistor is required. Here, a novel aqueous solution-processed Gd2O3 is suggested to be the solid electrolyte of synaptic transistors. The microstructure and the dielectric properties of Gd2O3 film are investigated, which shows the potential for the simulation of synaptic transmission. Then, the fully aqueous solution-processed In2O3 /Gd2O3 thin film transistor (TFT) is fabricated. The device exhibits an acceptable electrical performance with a small threshold voltage of 1.24 V, and a small subthreshold swing of 0.12 V/decade. The artificial synapse behavior is stimulated and the short-term plasticity of In2O3/Gd2O3 TFT is studied. The dependence of its excitatory post synaptic current on presynaptic pulse magnitude, width and frequency is verified. Besides, the synapse behavior of devices under continuous illumination stresses is investigated. The lights with different photon energy have different effects on the synaptic transmission, which is related to the ionization of oxygen vacancies. Our results demonstrate that fully aqueous solution-processed In2O3 TFT with Gd2O3 solid electrolyte is a candidate for the synaptic transistor.

10.
Plant Physiol ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857423

RESUMO

Rice (Oryza sativa) molecular breeding has gained considerable attention in recent years but inaccurate genome annotation hampers its progress and functional studies of the rice genome. In this study, we applied single-molecule long-read RNA sequencing (lrRNA_seq)-based proteogenomics to reveal the complexity of the rice transcriptome and its coding abilities. Surprisingly, approximately 60% of loci identified by lrRNA_seq are associated with natural antisense transcripts (NATs). The high-density genomic arrangement of NAT genes suggests their potential roles in the multifaceted control of gene expression. In addition, a large number of fusion and intergenic transcripts have been observed. Furthermore, a total of 906,456 transcript isoforms were identified, and 72.9% of the genes can generate splicing isoforms. 706,075 post-transcriptional events were subsequently categorized into ten subtypes, demonstrating the interdependence of post-transcriptional mechanisms that contribute to transcriptome diversity. Parallel short-read RNA sequencing indicated that lrRNA_seq has a superior capacity for the identification of longer transcripts. In addition, over 190,000 unique peptides belonging to 9,706 proteoforms/protein groups were identified, expanding the diversity of the rice proteome. Our findings indicate that the genome organization, transcriptome diversity, and coding potential of the rice transcriptome are far more complex than previously anticipated.

11.
Sci Rep ; 9(1): 19767, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875006

RESUMO

Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disease mediated by antibodies against the patient's red blood cells. However, the underlying mechanisms for antibody production are not fully understood. Previous studies of etiology and pathogenesis of AIHA mainly focus on autoreactive B cells that have escaped tolerance mechanisms. Few studies have reported the function of TFH and TFR cells in the process of AIHA. The present study aimed to explore the potential mechanism of TFH and TFR cells in the pathogenesis of AIHA. With the model of murine AIHA, increased ratios of TFH:TFR, elevated serum IL-21 and IL-6 levels, and upregulated Bcl-6 and c-Maf expression were reported. Also, adoptive transfer of purified CD4+CXCR5+CD25- T cells from immunized mice promoted the induction of autoantibody in the AIHA mouse model. Altogether, our data demonstrate the important role of TFH cells for control and induction of AIHA. In the light of the key contributions of TFH cells to the immune response in AIHA, strategies aimed at inhibiting the TFH development or function should be emphasized.

12.
ACS Nano ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31860277

RESUMO

Inspired by chasing-escaping behaviors of predator and swarming prey in nature, here we demonstrate a concept to create active micromotor systems from two species of passive microparticles with biomimetic predator-prey interactions. In this concept, the biomimetic predator-prey interactions are established in a binary particle system comprising the diffusiophoretic attractive microparticles (prey particles) and the diffusiophoretic repulsive ones (predator particles). In the absence of additional chemical fuels and external fields, the predator particles are attracted by and constantly chase the swarming prey particles, which, in response, escape from the former and show dynamic group reconfigurations because of the local repulsion. Based on this concept, various synthetic active micromotor systems have been demonstrated, including active ZnO-TiO2, Ag3PO4-TiO2, and ZnO-AgBr micromotor systems. As the predator and prey particles are powered by each other through the biomimetic predator-prey interactions, the concept proposed here provides an advanced method to develop not only a class of single micromotors powered by passive particles or "solid fuels" but also micromotor swarms capable of manipulating "moving cargo". In addition, it also illustrates a proof-of-concept implementation of intelligent micro/nanomotor systems composed of heterogeneous individuals with complementary or cooperative functions.

13.
Rice (N Y) ; 12(1): 79, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31707526

RESUMO

BACKGROUND: Proline (Pro) and γ-aminobutyric acid (GABA) play important roles in plant development and stress tolerance. However, the molecular components responsible for the transport of these molecules in rice remain largely unknown. RESULTS: Here we identified OsProT1 and OsProT3 as functional transporters for Pro and GABA. Transient expression of eGFP-OsProTs in plant protoplasts revealed that both OsProT1 and OsProT3 are localized to the plasma membrane. Ectopic expression in a yeast mutant demonstrated that both OsProT1 and OsProT3 specifically mediate transport of Pro and GABA with affinity for Pro in the low affinity range. qRT-PCR analyses suggested that OsProT1 was preferentially expressed in leaf sheathes during vegetative growth, while OsProT3 exhibited relatively high expression levels in several tissues, including nodes, panicles and roots. Interestingly, both OsProT1 and OsProT3 were induced by cadmium stress in rice shoots. CONCLUSIONS: Our results suggested that plasma membrane-localized OsProT1 and OsProT3 efficiently transport Pro and GABA when ectopically expressed in yeast and appear to be involved in various physiological processes, including adaption to cadmium stress in rice plants.

14.
Mol Immunol ; 116: 191-198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31710976

RESUMO

BACKGROUND: Scars affects the appearance and results in tissue damage. In this research, we preliminarily studied the function and mechanism of curcumin (CUR) on cell proliferation and soluble collagen synthesis in NIH-3T3 cells. METHODS: CCK-8 was used to detect the IC50 of CUR. Moreover, Western blot was used to measure the expression of cell proliferation-related, soluble collagen synthesis and pathway-related proteins. Sircol assay was determined the expression of soluble collagen. Furthermore, reverse transcription quantitative PCR (RT-qPCR) was used to determined miR-29a, α-smooth muscle aorta (α-SMA), soluble collagen 1 (Col 1) and Col 3 expression. RESULTS: CUR inhibited cell viability and proliferation-related proteins expression. Transforming growth factor-ß (TGFß1)-induced heightened the expression of proliferation-related proteins and soluble collagen synthesis-related proteins. CUR inhibited TGFß1-induced proliferation and soluble collagen synthesis. Furthermore, CUR positively related miR-29a and miR-29a mimic inhibited TGFß1-induced proliferation and soluble collagen synthesis. Besides, transfection with miR-29a inhibitor could partly reverse the effects of CUR. CUR inhibited the ERK1/2 and ß-catenin pathways and the miR-29a inhibitor reversed the above results. Otherwise, soluble collagen 1 (Col 1) partly reversed the effects of CUR on proliferation and soluble collagen synthesis and silenced Col 1/3 could inhibit ERK1/2 and ß-catenin signaling pathways. CONCLUSION: CUR restrained TGFß1-induced proliferation and soluble collagen synthesis in NIH-3T3 cells by up-regulation of miR-29a via ERK1/2 and ß-catenin signaling pathways.

15.
J Diabetes ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697444

RESUMO

BACKGROUND: Perioperative hyperglycemia was associated with postoperative infection, and proper management of perioperative glucose has become critical in improving the prognosis of patients. METHODS: A total of 1015 diabetic patients who underwent surgery and received insulin treatment for their hyperglycemia in our hospital were retrospectively reviewed. According to propensity matching, we obtained 253 pairs of patients from the group which received continuous subcutaneous insulin infusion (CSII) therapy (CSII group) and the group which received insulin injection therapy (non-CSII group). Perioperative glucose levels and corresponding outcomes were compared between the two groups. RESULTS: Compared with the non-CSII group, the CSII group had lower fasting and mean glucose levels, lower incidence of fever (operation day: 18.6% vs 10.2%; P = .014; first postoperative day: 55.1% vs 34.7%; P < .001), a positive rate of postoperative secretion culture (6.3% vs 1.2%; P = .004), and a shorter time of antibiotics use (total antibiotics use: P = .002; postoperative antibiotics use: P < .001) and hospital stays (P < .001). However, there was no difference in the total medical expenditure between the two groups (P = .499). Further analysis showed that CSII therapy was superior to multiple daily insulin injection (MDI) therapy in its effect on infection and other postoperative outcomes when 64 pairs of patients from the CSII group and MDI group were compared. CONCLUSIONS: CSII therapy provides better perioperative glucose control and a lower risk of postoperative infection without increasing the total medical expenditure. HIGHLIGHTS: In our study, we adopted propensity matching, which included 1015 patients and 30 types of surgeries. The results show that patients who receive continuous subcutaneous insulin infusion (CSII) therapy have a lower incidence of perioperative fever, a lower positive rate of postoperative secretion culture, and a shorter duration of antibiotic use. These results indicate that CSII therapy reduces the risk of postoperative infection and improves the prognosis of patients.

16.
Planta ; 251(1): 22, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781953

RESUMO

MAIN CONCLUSION: This study unravels the transcriptional response of a highly productive faba bean cultivar under vernalization treatment. Faba bean (Vicia faba L.) is a member of the Leguminosae family and an important food crop worldwide providing valuable nutrients for humans. However, genome-wide studies and comprehensive sequencing resources of faba bean remain limited. Vernalization is crucial for enhanced yields in a number of winter-sown crops. However, the effects of vernalization on faba bean remain unknown. In this study, we generated a high-quality transcriptome assembly and functional annotation source for vernalized faba bean (Vicia faba L.) cv. Tongxian-2, a domesticated cultivar from southern China. A total of 369.9 million clean Illumina paired-end RNA-Seq reads were generated, and the transcriptome was assembled into 68,683 unigene sequences, with an average length of 1018 bp and an N50 of 1652 bp. Comprehensive functional annotation provided putative functional descriptions for more than 70% of the faba bean transcripts. We annotated a total of 1560 faba bean transcripts encoding transcription factors (TFs) belonging to 55 distinct TF families. The bHLH (168 transcripts), ERF (123 transcripts) and WRKY (105 transcripts) contained the largest number of TFs in response to vernalization. Genome-wide transcript changes comparing vernalized and unvernalized seedlings were investigated using bioinformatics approaches, which revealed a strong repression of photosynthesis and carbon metabolism, while genes participating in 'response to stress' were significantly induced. We also specifically identified vernalization-induced twenty-two 'pollen-pistil interaction' genes. A detailed functional annotation and expression profile analyses unveiled a number of protein kinases, which were specifically induced in vernalized seedlings. We also identified a total of 6852 simple sequence repeats (SSRs) in 6552 transcripts, representing a valuable genomic molecular marker resource for faba bean. In summary, this study provides new insights into the vernalization process in this economically valuable crop. The transcriptome data obtained provides us with a valuable candidate gene resource for future functional and molecular breeding studies. These data will contribute to the genome annotation for ensuing genome projects.

17.
Phys Chem Chem Phys ; 21(48): 26549-26556, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31782443

RESUMO

Compared with other morphological nanomaterials, nanorods have many unique properties that are closely related to their thermal stability. However, current studies on melting thermodynamic theory of nanorods are still not perfect, and the mechanism and the quantitative regularities of the effect of size of nanorods on melting thermodynamics still remain unclear. Herein, we proposed a melting model of nanorods, derived the thermodynamic relations (free of any adjustable parameters) between the melting temperature, melting enthalpy, and melting entropy, respectively, and the radius of nanorods, and discussed the mechanism of the effect of nanorods and the size dependences of melting thermodynamic properties. Experimentally, taking the melting of Se nanorods as an experimental system, Se nanorods with different diameters were prepared by a Na2SeSO3 disproportionation method, and then the melting temperature and melting thermodynamic properties were determined by differential scanning calorimetry. The effects of the diameter of Se nanorods on the melting temperature and the melting thermodynamic properties were obtained. The experimental results are consistent with the theoretical relations. Both theoretical and experimental results demonstrate that the radius and length of nanorods have significant effects on the melting temperature and the melting thermodynamic properties; for nanorods with a large aspect ratio, the main factors of influence are interfacial tension and radius. Compared with spherical nanoparticles with the same radius, the reduced values of the melting temperature and the thermodynamic properties of nanorods are just half of those corresponding to spherical nanoparticles; the melting temperature, the melting enthalpy, and the melting entropy decrease with the decrease in the radius, and when the radius exceeds 10 nm, these physical quantities are all linearly related to the reciprocal of the radius. The theory can describe the quantitative size-dependent melting thermodynamic properties of nanorods, explain and predict the melting behaviors of nanorods.

18.
Planta ; 251(1): 14, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776670

RESUMO

MAIN CONCLUSION: This study provides new insights that alternative splicing participates with transcriptional control in defense responses to Colletotrichum sublineola in sorghum In eukaryotic organisms, alternative splicing (AS) is an important post-transcriptional mechanism to generate multiple transcript isoforms from a single gene. Protein variants translated from splicing isoforms may have altered molecular characteristics in signal transduction and metabolic activities. However, which transcript isoforms will be translated into proteins and the biological functions of the resulting proteoforms are yet to be identified. Sorghum is one of the five major cereal crops, but its production is severely affected by fungal diseases. For example, sorghum anthracnose caused by Colletotrichum sublineola greatly reduces grain yield and biomass production. In this study, next-generation sequencing technology was used to analyze C. sublineola-inoculated sorghum seedlings compared with mock-inoculated control. It was identified that AS regulation may be as important as traditional transcriptional control during defense responses to fungal infection. Moreover, several genes involved in flavonoid and phenylpropanoid biosynthetic pathways were found to undergo multiple AS modifications. Further analysis demonstrated that non-conventional targets of both 5'- and 3'-splice sites were alternatively used in response to C. sublineola infection. Splicing factors were also affected at both transcriptional and post-transcriptional levels. As the first transcriptome report on C. sublineola infected sorghum, our work also suggested that AS plays crucial functions in defense responses to fungal invasion.

19.
Org Biomol Chem ; 17(47): 10073-10087, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31750499

RESUMO

We developed a general and sustainable approach for the regioselective deoxygenative chalcogenation of 7-azindole N-oxides; the combination of an internal oxidant and a green solvent has been used successfully for the synthesis of mono- and dichalcogenyl 7-azaindoles which are of pharmaceutical interest. The regioselectivity is tunable by the variation of the reaction conditions. I2/PEG was established as an efficient and reusable catalytic system for C-H chalcogenation. This developed methodology has great potential for practical utility, with a broad substrate scope, green reaction conditions, and operational simplicity.

20.
Oncogene ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754213

RESUMO

EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients' outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.

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