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2.
ArXiv ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34815983

RESUMO

Artificial intelligence (AI) provides a promising substitution for streamlining COVID-19 diagnoses. However, concerns surrounding security and trustworthiness impede the collection of large-scale representative medical data, posing a considerable challenge for training a well-generalised model in clinical practices. To address this, we launch the Unified CT-COVID AI Diagnostic Initiative (UCADI), where the AI model can be distributedly trained and independently executed at each host institution under a federated learning framework (FL) without data sharing. Here we show that our FL model outperformed all the local models by a large yield (test sensitivity /specificity in China: 0.973/0.951, in the UK: 0.730/0.942), achieving comparable performance with a panel of professional radiologists. We further evaluated the model on the hold-out (collected from another two hospitals leaving out the FL) and heterogeneous (acquired with contrast materials) data, provided visual explanations for decisions made by the model, and analysed the trade-offs between the model performance and the communication costs in the federated training process. Our study is based on 9,573 chest computed tomography scans (CTs) from 3,336 patients collected from 23 hospitals located in China and the UK. Collectively, our work advanced the prospects of utilising federated learning for privacy-preserving AI in digital health.

3.
Front Genet ; 12: 705753, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721519

RESUMO

The Hui minority is predominantly composed of Chinese-speaking Islamic adherents distributed throughout China, of which the individuals are mainly concentrated in Northwest China. In the present study, we employed the length and sequence polymorphisms-based typing system of 231 molecular markers, i.e., amelogenin, 22 phenotypic-informative single nucleotide polymorphisms (PISNPs), 94 identity-informative single nucleotide polymorphisms (IISNPs), 24 Y-chromosomal short tandem repeats (Y-STRs), 56 ancestry-informative single nucleotide polymorphisms (AISNPs), 7 X-chromosomal short tandem repeats (X-STRs), and 27 autosomal short tandem repeats (A-STRs), into 90 unrelated male individuals from the Chinese Northwest Hui group to comprehensively explore its forensic characteristics and genetic background. Total of 451 length-based and 652 sequence-based distinct alleles were identified from 58 short tandem repeats (STRs) in 90 unrelated Northwest Hui individuals, denoting that the sequence-based genetic markers could pronouncedly provide more genetic information than length-based markers. The forensic characteristics and efficiencies of STRs and IISNPs were estimated, both of which externalized high polymorphisms in the Northwest Hui group and could be further utilized in forensic investigations. No significant departure from the Hardy-Weinberg equilibrium (HWE) expectation was observed after the Bonferroni correction. Additionally, four group sets of reference population data were exploited to dissect the genetic background of the Northwest Hui group separately from different perspectives, which contained 26 populations for 93 IISNPs, 58 populations for 17 Y-STRs, 26 populations for 55 AISNPs (raw data), and 109 populations for 55 AISNPs (allele frequencies). As a result, the analyses based on the Y-STRs indicated that the Northwest Hui group primarily exhibited intimate genetic relationships with reference Hui groups from Chinese different regions except for the Sichuan Hui group and secondarily displayed close genetic relationships with populations from Central and West Asia, as well as several Chinese groups. However, the AISNP analyses demonstrated that the Northwest Hui group shared more intimate relationships with current East Asian populations apart from reference Hui group, harboring the large proportion of ancestral component contributed by East Asia.

4.
ACS Appl Mater Interfaces ; 13(46): 55403-55411, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34756010

RESUMO

To reduce synthetic cost of the classic fluorinated bithienyl benzodithiophene (BDTT-F) unit, here, an alpha-fluorinated bithienyl benzodithiophene unit, namely, α-BDTT-F (F atom in the α position of the lateral thiophene unit), is developed by the isomerization strategy of exchanging the positions of the F atom and flexible alkyl chain on the lateral thiophene unit of the BDTT-F unit. The α-BDTT-F unit was synthesized with less synthetic steps, higher synthetic yield, and less purification times from the same raw materials as those of the BDTT-F unit, thus with low synthetic cost. Theoretical calculation indicates that the α-BDTT-F unit possesses a similar twisted conformation and electronic structures as those of the BDTT-F unit. The α-BDTT-F-based polymer α-PBQ10 exhibits similar light absorption and energy levels as those of the corresponding BDTT-F-based polymer PBQ10 but marginally increased molecular aggregation and stronger hole transport than PBQ10. In consequence, the α-PBQ10:Y6-based polymer solar cell demonstrates a slightly enhanced power conversion efficiency (PCE) of 16.26% compared with that of the PBQ10:Y6-based device (PCE = 16.23%). Also, the PCE is further improved to 16.77% through subtle microscopic morphology regulation of the photoactive layer with the fullerene derivative indene-C60 bisadduct as the third component. This work provides new ideas for the design of low-cost and high-efficiency photovoltaic molecules.

5.
Int J Gynecol Cancer ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799419

RESUMO

OBJECTIVE: To assess the strategy and value of centralized surveillance of hydatidiform mole at a regional hospital in China and to investigate the necessity of prophylactic chemotherapy for high-risk complete hydatidiform mole. METHODS: Between February 2013 and February 2020, all women with hydatidiform mole in Dalian Women's and Children's Medical Center (Group) were registered for surveillance and treatment when indicated. Women with complete hydatidiform mole were categorized into low-risk and high-risk groups according to the criteria from Song Hongzhao's trophoblastic neoplasia. Outcomes and treatments were analyzed retrospectively. RESULTS: In total, 703 women with hydatidiform mole were registered for surveillance with a follow-up rate of 97.9% (688/703). 680 women were enrolled and 52 (7.6%) developed post-molar gestational trophoblastic neoplasia, all with low-risk International Federation of Gynecology and Obstetrics (FIGO) scores 0-5. Post-molar gestational trophoblastic neoplasia was diagnosed in 12.3% (51/413) of patients with complete hydatidiform moles and 0.4% (1/263) of patients were diagnosed with partial hydatidiform moles (χ2=32.415, p<0.001). Post-molar gestational trophoblastic neoplasia was diagnosed in 27.7% (28/101) of the high-risk complete hydatidiform mole group and in 7.4% (23/312) of the low-risk complete hydatidiform mole group (χ2=29.196, p<0.001). No difference in the pre-treatment assessments of patients with post-molar gestational trophoblastic neoplasia was found between the low-risk and high-risk complete hydatidiform mole groups (all p>0.05). All 52 patients with post-molar gestational trophoblastic neoplasia were cured, with a complete response rate of 61.2% (30/49) with first-line single-agent chemotherapy. CONCLUSIONS: A centralized hydatidiform mole surveillance program is feasible and effective and may improve the prognosis of patients with post-molar gestational trophoblastic neoplasia. Prophylactic chemotherapy is not recommended for women with high-risk complete hydatidiform mole with adequate surveillance.

6.
Cell Death Dis ; 12(10): 906, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611130

RESUMO

Hematopoietic stem cells (HSCs) possess the potential for self-renew and the capacity, throughout life, to differentiate into all blood cell lineages. Yet, the mechanistic basis for HSC development remains largely unknown. In this study, we characterized a zebrafish smu471 mutant with hematopoietic stem/progenitor cell (HSPC) defects and found that sart3 was the causative gene. RNA expression profiling of the sart3smu471 mutant revealed spliceosome and p53 signaling pathway to be the most significantly enriched pathways in the sart3smu471 mutant. Knock down of p53 rescued HSPC development in the sart3smu471 mutant. Interestingly, the p53 inhibitor, mdm4, had undergone an alternative splicing event in the mutant. Restoration of mdm4 partially rescued HSPC deficiency. Thus, our data suggest that HSPC proliferation and maintenance require sart3 to ensure the correct splicing and expression of mdm4, so that the p53 pathway is properly inhibited to prevent definitive hematopoiesis failure. This study expands our knowledge of the regulatory mechanisms that impact HSPC development and sheds light on the mechanistic basis and potential therapeutic use of sart3 in spliceosome-mdm4-p53 related disorders.

7.
Phys Chem Chem Phys ; 23(34): 18784-18793, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34612417

RESUMO

Graphene has been used as a conductive substrate to improve the electrochemical performance of layered VS2 as an anode material for lithium-ion batteries. However, there is still a lack of in-depth understanding of the synergistic effect between the layered VS2 and graphene, which contributes to the enhanced performance of Li/Na-ion batteries. In this work, using first-principles calculations, we have systematically studied the VS2/graphene heterostructure as an anode material for Li/Na-ion batteries. Our results show that the VS2/graphene heterostructure is a promising anode material with good structural stability, high adsorption strength, high stiffness, intrinsic metallic characteristic after Li/Na adsorption, high theoretical specific capacity, shallow averaged open-circuit voltage and ultra-low ion diffusion barriers. The diffusion barriers are found to be 0.03 eV (Li) and 0.08 eV (Na), superior to that of the widely studied heterostructure materials, which guarantees an extremely fast Li/Na diffusion rate during charge/discharge cycling. The anode overall open-circuit voltages for the Li/Na-ion batteries are calculated to be as low as 0.65 and 0.46 V, and the maximum theoretical storage capacity is 771 and 578 mA h g-1, respectively. The above results provide valuable insights into the experimental set-up of the VS2/graphene nanocomposite anode material for ultra-high rate and high-specific capacity Li/Na-ion batteries.

8.
Nat Metab ; 3(10): 1400-1414, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34663975

RESUMO

5-diphosphoinositol pentakisphosphate (5-IP7) is a signalling metabolite linked to various cellular processes. How extracellular stimuli elicit 5-IP7 signalling remains unclear. Here we show that 5-IP7 in ß cells mediates parasympathetic stimulation of synaptotagmin-7 (Syt7)-dependent insulin release. Mechanistically, vagal stimulation and activation of muscarinic acetylcholine receptors triggers Gαq-PLC-PKC-PKD-dependent signalling and activates IP6K1, the 5-IP7 synthase. Whereas both 5-IP7 and its precursor IP6 compete with PIP2 for binding to Syt7, Ca2+ selectively binds 5-IP7 with high affinity, freeing Syt7 to enable fusion of insulin-containing vesicles with the cell membrane. ß-cell-specific IP6K1 deletion diminishes insulin secretion and glucose clearance elicited by muscarinic stimulation, whereas mice carrying a phosphorylation-mimicking, hyperactive IP6K1 mutant display augmented insulin release, congenital hyperinsulinaemia and obesity. These phenotypes are absent in mice lacking Syt7. Our study proposes a new conceptual framework for inositol pyrophosphate physiology in which 5-IP7 acts as a GPCR second messenger at the interface between peripheral nervous system and metabolic organs, transmitting Gq-coupled GPCR stimulation to unclamp Syt7-dependent, and perhaps other, exocytotic events.

10.
Cancer Res ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654723

RESUMO

Invasive mucinous lung adenocarcinoma (IMA) is a subtype of lung adenocarcinoma with a strong invasive ability. IMA frequently carries "undruggable" KRAS mutations, highlighting the need for new molecular targets and therapies. Nuclear receptor HNF4α is abnormally enriched in invasive mucinous lung adenocarcinoma (IMA), but the potential of HNF4α to be a therapeutic target for IMA remains unknown. Here, we report that P2 promoter-driven HNF4α expression promotes IMA growth and metastasis. Mechanistically, HNF4α transactivated lncRNA BC200, which acted as a scaffold for mRNA binding protein FMR1. BC200 promoted the ability of FMR1 to bind and regulate stability of cancer-related mRNAs and HNF4α mRNA, forming a positive feedback circuit. Mycophenolic acid, the active metabolite of FDA-approved drug mycophenolate mofetil, was identified as an HNF4α antagonist exhibiting anti-IMA activities in vitro and in vivo. This study reveals the role of a HNF4α-BC200-FMR1 positive feedback loop in promoting mRNA stability during IMA progression and metastasis, providing a targeted therapeutic strategy for IMA.

11.
Elife ; 102021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467854

RESUMO

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca2+ ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale transitions of seven-transmembrane domains, and inter- and intrasubunit conformational changes of seven-transmembrane domains to accommodate downstream transducers. Our results reveal the structural basis for activation mechanisms of CaSR and clarify the mode of action of Ca2+ ions and L-amino acid leading to the activation of the receptor.


Assuntos
Receptores de Detecção de Cálcio/metabolismo , Cálcio/metabolismo , Microscopia Crioeletrônica , Dimerização , Homeostase , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Receptores de Detecção de Cálcio/agonistas , Receptores de Detecção de Cálcio/química , Transdução de Sinais , Triptofano/análogos & derivados
12.
J Econ Entomol ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34568947

RESUMO

Alternative splicing of protein coding genes plays a profound role in phenotypic variation for many eukaryotic organisms. The development of high-throughput sequencing and bioinformatics algorithms provides the possibility of genome-wide identification of alternative splicing events in eukaryotes. However, for the brown planthopper Nilaparvata lugens, a destructive pest of rice crops, whole-genome distribution of alternative splicing events and the role of alternative splicing in the phenotypic plasticity of virulence have not previously been estimated. Here, we developed an analysis pipeline to identify alternative splicing events in the genome of N. lugens. Differential expression analysis and functional annotation were performed on datasets related to different virulence phenotypes. In total, 27,880 alternative splicing events corresponding to 9,787 multi-exon genes were detected in N. lugens. Among them, specifically expressed alternative splicing transcripts in the virulent Mudgo population were enriched in metabolic process categories, while transcripts in the avirulent TN1 population were enriched in regulator activity categories. In addition, genes encoding odorant receptor, secreted saliva protein and xenobiotic metabolic P450 monooxygenase showed different splicing patterns between Mudgo population and TN1 population. Host change experiment also revealed that an isoform of a P450 gene could be specially induced by the stimulation of resistant rice variety Mudgo. This research pioneered a genome-wide study of alternative gene splicing in the rice brown planthopper. Differences in alternative splicing between virulent and avirulent populations indicated that alternative splicing might play an important role in the formation of virulence phenotypes in N. lugens.

13.
Mycoses ; 64(11): 1422-1428, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34553417

RESUMO

BACKGROUND: Oral chronic hyperplastic candidiasis (CHC) is the most uncommon type of oral candidiasis with diverse manifestations. Up to date the diagnosis, long-term management and prognosis of this oral potentially malignant disorder remain obscure. OBJECTIVES: The aim of this study was to provide the recommendations guiding the diagnostic procedure, clinical management and prognosis assessment of CHC. METHODS: A retrospective cohort study was performed during January 2015 to April 2021 involving patients with a definite diagnosis of CHC in the Department of Oral Medicine of Peking University School and Hospital of Stomatology. Demographic features, clinical and histopathological features, treatment protocols and follow-ups including malignancy transformation were analysed. RESULTS: Fourty eight CHC patients were collected and reviewed, with a male-to-female ratio of 2.69:1. The average age at diagnosis was 54.92 ± 9.79 (36-80) years old. Clinically, the multiform oral lesions were diverse and frequently presented as white plaque and erythematous lesions. As a result, the initial diagnostic accordance rate was only 54.17%, and the most common presumptive initial diagnoses were oral lichen planus (22.92%), oral leukoplakia (20.83%) and traumatic lesion (2.08%). Histopathologically, ten (20.83%) patients had varying degrees of epithelial dysplasia, and two (4.17%) patients had malignant transformation with a mean transformation time of 6.5 ± 6.36 months. Among the 28 patients who underwent fungal culture, 24 patients were exclusively infected by Candida albicans, with two patients each mixed infected by C glabrata and C tropicalis, respectively. Notably, treatment with fluconazole had the lower recurrence rate compared with topical nystatin. CONCLUSIONS: The diagnosis and management of CHC remain a challenge due to its polymorphic clinical presentations, chronic progression and potential of malignant transformation.


Assuntos
Candidíase Mucocutânea Crônica/patologia , Candidíase Mucocutânea Crônica/terapia , Neoplasias Bucais/etiologia , Neoplasias Bucais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
J Comput Chem ; 42(31): 2213-2220, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34486140

RESUMO

The recently discovered hybrid organic-inorganic perovskites have been suggested for high-performance optoelectronic applications. Owing to the mechanical flexibility of these compounds, they demonstrate structural fluctuation at finite temperatures that have been widely discussed with respect to their optical properties. However, the effect of temperature-induced structural fluctuation is not clear until now, with respect to the equally important charge transport properties. In the present study, through ab initio molecular dynamics simulations of cubic-phase CH3 NH3 PbI3 at different temperatures, the temperature-dependent electronic structure and charge carrier transport properties are examined. Compared with the significant structural fluctuation of organic cations, the structural change of the inorganic framework is minor. In addition, because the band edge states at R point are mainly influenced by the anti-bonding character of the Pb-I bond, CH3 NH3 PbI3 demonstrates relatively small deformation potentials as well as low temperature dependence of band gaps (ΔEg ≈ 50 meV from 330 K to 400 K) and electron-phonon coupling strengths, despite the large structural fluctuation of organic cations. Furthermore, the effective mass of the valence band increases with the increase of temperature. The predicted mobilities of CH3 NH3 PbI3 can reach above 75 cm2 V-1  s-1 near room temperature, exhibiting an appropriate optoelectronic potential, while the temperature dependence is steeper than T-1.5 of the traditional semiconductors because of the enhanced effective masses.

15.
Extremophiles ; 25(5-6): 483-492, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34533626

RESUMO

Two extremely halophilic archaea, isolates SYSU A00711T and SYSU A00630, were isolated from a sediment soil sample collected from the Aiding lake, China. Cells of these isolates were cocci, non-motile and stained Gram-negative. They grew optimally at 37 °C, with 20-22% NaCl (w/v) and at pH 7.5-8.0. Cells lysed in distilled water. Major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, mannosyl glucosyl diether, sulfated mannosyl glucosyl diether, and two unidentified glycolipids. Pairwise sequence comparison revealed that isolates SYSU A00711T and SYSU A00630 were closely related to Halegenticoccus soli SYSU A9-0T (94.1 and 94.0% 16S rRNA gene sequence similarities; 94.0 and 94.2% rpoB' gene similarities, respectively). The overall genomic relatedness indices values between the two isolates and Halegenticocus soli SYSU A9-0 T were: AAI, both 79.6%; ANI, 84.6 and 84.5%; dDDH, 32.5 and 26.3%, respectively. Phylogenetic trees based on the 16S rRNA gene, rpoB' gene, and genome sequences demonstrated a robust clade of these two isolates with Halegenticoccus soli SYSU A9-0T. The DNA G + C contents of these two isolates are both 64.7% (genome method). Based on the differences in phenotypic, chemotaxonomic, and phylogenetic properties, isolates SYSU A00711T and SYSU A00630 are characterized to represent a novel species in the genus Halegenticoccus, for which the name Halegenticoccus tardaugens sp. nov. is proposed. The type strain of the species Halegenticoccus tardaugens is SYSU A00711T (= KCTC 4245T = CGMCC 1.15768T).


Assuntos
Halobacteriaceae , Solo , China , DNA Arqueal , Halobacteriaceae/genética , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
16.
Sci Data ; 8(1): 236, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493728

RESUMO

Since the proposal of the "Materials Genome Initiative", several material databases have emerged and advanced many materials fields. In this work, we present the Materials Informatics Platform with Three-Dimensional Structures (MIP-3d). More than 80,000 structural entries, mainly from the inorganic crystal structural database, are included in MIP-3d. Density functional theory calculations are carried out for over 30,000 entries in the database, which contain the relaxed crystal structures, density of states, and band structures. The calculation of the equations of state and sound velocities is performed for over 12,000 entries. Notably, for entries with band gap values larger than 0.3 eV, the band degeneracies for the valence band maxima and the conduction band minima are analysed. The electrical transport properties for approximately 4,400 entries are also calculated and presented in MIP-3d under the constant electron-phonon coupling approximation. The calculations of the band degeneracies and electrical transport properties make MIP-3d a database specifically designed for thermoelectric applications.

17.
Innovation (N Y) ; 2(2): 100101, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34557752

RESUMO

How magnetism affects the Seebeck effect is an important issue of wide concern in the thermoelectric community but remains elusive. Based on a thermodynamic analysis of spin degrees of freedom on varied d-electron-based ferromagnets and antiferromagnets, we demonstrate that in itinerant or partially itinerant magnetic compounds there exists a generic spin contribution to the Seebeck effect over an extended temperature range from slightly below to well above the magnetic transition temperature. This contribution is interpreted as resulting from transport spin entropy of (partially) delocalized conducting d electrons with strong thermal spin fluctuations, even semiquantitatively in a single-band case, in addition to the conventional diffusion part arising from their kinetic degrees of freedom. As a highly generic effect, the spin-dependent Seebeck effect might pave a feasible way toward efficient "magnetic thermoelectrics."

18.
Cell Prolif ; 54(9): e13105, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34382270

RESUMO

OBJECTIVES: The nano-hydroxyapatite (nHAp) is widely used to develop imaging probes and drug carriers due to its excellent bioactivity and biocompatibility. However, traditional methods usually need cumbersome and stringent conditions such as high temperature and post-modification to prepare the functionalized nHAp, which do not benefit the particles to enter cells due to the increased particle size. Herein, a biomimetic synthesis strategy was explored to achieve the AS1411-targeted tumour dual-model bioimaging using DNA aptamer AS1411 as a template. Then, the imaging properties and the biocompatibility of the synthesized AS-nFAp:Gd/Tb were further investigated. MATERIALS AND METHODS: The AS-nFAp:Gd/Tb was prepared under mild conditions through a one-pot procedure with AS1411 as a template. Besides, the anticancer drug DOX was loaded to AS-nFAp:Gd/Tb so as to achieve the establishment of a multifunctional nano-probe that integrated the tumour diagnosis and treatment. The AS-nFAp:Gd/Tb was characterized by transmission electron microscopy (TEM), energy disperse X-ray Spectroscopy (EDS) mapping, X-ray photoelectron spectroscopy (XPS) spectrum, X-ray diffraction (XRD), fourier-transformed infrared (FTIR) spectroscopy, capillary electrophoresis analyses, zeta potential and particle sizes. The in vitro magnetic resonance imaging (MRI) and fluorescence imaging were performed on an MRI system and a confocal laser scanning microscope, respectively. The potential of the prepared multifunctional nHAp for a targeted tumour therapy was investigated by a CCK-8 kit. And the animal experiments were conducted on the basis of the guidelines approved by the Animal Care and Use Committee of Sichuan University, China. RESULTS: In the presence of AS1411, the as-prepared AS-nFAp:Gd/Tb presented a needle-like morphology with good monodispersity and improved imaging performance. Furthermore, due to the specific binding between AS1411 and nucleolin up-expressed in cancer cells, the AS-nFAp:Gd/Tb possessed excellent AS1411-targeted fluorescence and MRI imaging properties. Moreover, after loading chemotherapy drug DOX, in vitro and in vivo studies showed that DOX@AS-nFAp:Gd/Tb could effectively deliver DOX to tumour tissues and exert a highly effective tumour inhibition without systemic toxicity compared with pure DOX. CONCLUSIONS: The results indicated that the prepared multifunctional nHAp synthesized by a novel biomimetic strategy had outstanding capabilities of recognition and treatment for the tumour and had good biocompatibility; hence, it might have a potential clinical application in the future.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/química , Durapatita/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Aptâmeros de Nucleotídeos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Camundongos , Camundongos Nus , Microscopia Eletrônica de Transmissão/métodos , Oligodesoxirribonucleotídeos/farmacologia , Tamanho da Partícula
19.
Development ; 148(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34373913

RESUMO

Neutrophils are the most abundant vertebrate leukocytes and they are essential to host defense. Despite extensive investigation, the molecular network controlling neutrophil differentiation remains incompletely understood. GFI1 is associated with several myeloid disorders, but its role and the role of its co-regulators in granulopoiesis and pathogenesis are far from clear. Here, we demonstrate that zebrafish gfi1aa deficiency induces excessive neutrophil progenitor proliferation, accumulation of immature neutrophils from the embryonic stage, and some phenotypes similar to myelodysplasia syndrome in adulthood. Both genetic and epigenetic analyses demonstrate that immature neutrophil accumulation in gfi1aa-deficient mutants is due to upregulation of cebpa transcription. Increased transcription was associated with Lsd1-altered H3K4 methylation of the cebpa regulatory region. Taken together, our results demonstrate that Gfi1aa, Lsd1 and cebpa form a regulatory network that controls neutrophil development, providing a disease progression-traceable model for myelodysplasia syndrome. Use of this model could provide new insights into the molecular mechanisms underlying GFI1-related myeloid disorders as well as a means by which to develop targeted therapeutic approaches for treatment.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hematopoese/genética , Histona Desmetilases/metabolismo , Neutrófilos/citologia , Proteínas de Peixe-Zebra/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular , Proliferação de Células , Proteínas de Ligação a DNA/deficiência , Embrião não Mamífero , Epigênese Genética , Células Precursoras de Granulócitos/citologia , Células Precursoras de Granulócitos/metabolismo , Histona Desmetilases/genética , Neutrófilos/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética
20.
PLoS Genet ; 17(8): e1009693, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34351909

RESUMO

The ubiquitin-proteasome system plays important roles in various biological processes as it degrades the majority of cellular proteins. Adequate proteasomal degradation of crucial transcription regulators ensures the proper development of neutrophils. The ubiquitin E3 ligase of Growth factor independent 1 (GFI1), a key transcription repressor governing terminal granulopoiesis, remains obscure. Here we report that the deficiency of the ring finger protein Interferon regulatory factor 2 binding protein 2a (Irf2bp2a) leads to an impairment of neutrophils differentiation in zebrafish. Mechanistically, Irf2bp2a functions as a ubiquitin E3 ligase targeting Gfi1aa for proteasomal degradation. Moreover, irf2bp2a gene is repressed by Gfi1aa, thus forming a negative feedback loop between Irf2bp2a and Gfi1aa during neutrophils maturation. Different levels of GFI1 may turn it into a tumor suppressor or an oncogene in malignant myelopoiesis. Therefore, discovery of certain drug targets GFI1 for proteasomal degradation by IRF2BP2 might be an effective anti-cancer strategy.


Assuntos
Proteínas de Ligação a DNA/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/crescimento & desenvolvimento , Animais , Proteínas de Ligação a DNA/metabolismo , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Células HL-60 , Humanos , Leucopoese , Masculino , Proteólise , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
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