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1.
Nature ; 608(7923): 569-577, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35922514

RESUMO

A major challenge in human genetics is to identify the molecular mechanisms of trait-associated and disease-associated variants. To achieve this, quantitative trait locus (QTL) mapping of genetic variants with intermediate molecular phenotypes such as gene expression and splicing have been widely adopted1,2. However, despite successes, the molecular basis for a considerable fraction of trait-associated and disease-associated variants remains unclear3,4. Here we show that ADAR-mediated adenosine-to-inosine RNA editing, a post-transcriptional event vital for suppressing cellular double-stranded RNA (dsRNA)-mediated innate immune interferon responses5-11, is an important potential mechanism underlying genetic variants associated with common inflammatory diseases. We identified and characterized 30,319 cis-RNA editing QTLs (edQTLs) across 49 human tissues. These edQTLs were significantly enriched in genome-wide association study signals for autoimmune and immune-mediated diseases. Colocalization analysis of edQTLs with disease risk loci further pinpointed key, putatively immunogenic dsRNAs formed by expected inverted repeat Alu elements as well as unexpected, highly over-represented cis-natural antisense transcripts. Furthermore, inflammatory disease risk variants, in aggregate, were associated with reduced editing of nearby dsRNAs and induced interferon responses in inflammatory diseases. This unique directional effect agrees with the established mechanism that lack of RNA editing by ADAR1 leads to the specific activation of the dsRNA sensor MDA5 and subsequent interferon responses and inflammation7-9. Our findings implicate cellular dsRNA editing and sensing as a previously underappreciated mechanism of common inflammatory diseases.


Assuntos
Adenosina Desaminase , Predisposição Genética para Doença , Doenças do Sistema Imunitário , Inflamação , Edição de RNA , RNA de Cadeia Dupla , Adenosina/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Elementos Alu/genética , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Estudo de Associação Genômica Ampla , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Inosina/metabolismo , Helicase IFIH1 Induzida por Interferon/metabolismo , Interferons/genética , Interferons/imunologia , Locos de Características Quantitativas/genética , Edição de RNA/genética , RNA de Cadeia Dupla/genética , Proteínas de Ligação a RNA/metabolismo
2.
Proc Natl Acad Sci U S A ; 120(23): e2101243120, 2023 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-37252978

RESUMO

Iron-based redox-active minerals are ubiquitous in soils, sediments, and aquatic systems. Their dissolution is of great importance for microbial impacts on carbon cycling and the biogeochemistry of the lithosphere and hydrosphere. Despite its widespread significance and extensive prior study, the atomic-to-nanoscale mechanisms of dissolution remain poorly understood, particularly the interplay between acidic and reductive processes. Here, we use in situ liquid-phase-transmission electron microscopy (LP-TEM) and simulations of radiolysis to probe and control acidic versus reductive dissolution of akaganeite (ß-FeOOH) nanorods. Informed by crystal structure and surface chemistry, the balance between acidic dissolution at rod tips and reductive dissolution at rod sides was systematically varied using pH buffers, background chloride anions, and electron beam dose. We find that buffers, such as bis-tris, effectively inhibited dissolution by consuming radiolytic acidic and reducing species such as superoxides and aqueous electrons. In contrast, chloride anions simultaneously suppressed dissolution at rod tips by stabilizing structural elements while promoting dissolution at rod sides through surface complexation. Dissolution behaviors were systematically varied by shifting the balance between acidic and reductive attacks. The findings show LP-TEM combined with simulations of radiolysis effects can provide a unique and versatile platform for quantitatively investigating dissolution mechanisms, with implications for understanding metal cycling in natural environments and the development of tailored nanomaterials.

3.
Nat Mater ; 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39448841

RESUMO

Metal carbonates, which are ubiquitous in the near-surface mineral record, are a major product of biomineralizing organisms and serve as important targets for capturing anthropogenic CO2 emissions. However, pathways of carbonate mineralization typically diverge from classical predictions due to the involvement of disordered precursors, such as the dense liquid phase (DLP), yet little is known about DLP formation or solidification processes. Using in situ methods we report that a highly hydrated bicarbonate DLP forms via liquid-liquid phase separation and transforms into hollow hydrated amorphous CaCO3 particles. Acidic proteins and polymers extend DLP lifetimes while leaving the pathway and chemistry unchanged. Molecular simulations suggest that the DLP forms via direct condensation of solvated Ca²+⋅(HCO3-)2 complexes that react due to proximity effects in the confined DLP droplets. Our findings provide insight into CaCO3 nucleation that is mediated by liquid-liquid phase separation, advancing the ability to direct carbonate mineralization and elucidating an often-proposed complex pathway of biomineralization.

4.
Plant Physiol ; 196(1): 95-111, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-38630866

RESUMO

Ginkgo (Ginkgo biloba L.) is one of the earliest extant species in seed plant phylogeny. Embryo development patterns can provide fundamental evidence for the origin, evolution, and adaptation of seeds. However, the architectural and morphological dynamics during embryogenesis in G. biloba remain elusive. Herein, we obtained over 2,200 visual slices from 3 stages of embryo development using micro-computed tomography imaging with improved staining methods. Based on 3-dimensional (3D) spatiotemporal pattern analysis, we found that a shoot apical meristem with 7 highly differentiated leaf primordia, including apical and axillary leaf buds, is present in mature Ginkgo embryos. 3D rendering from the front, top, and side views showed 2 separate transport systems of tracheids located in the hypocotyl and cotyledon, representing a unique pattern of embryogenesis. Furthermore, the morphological dynamic analysis of secretory cavities indicated their strong association with cotyledons during development. In addition, we identified genes GbLBD25a (lateral organ boundaries domain 25a), GbCESA2a (cellulose synthase 2a), GbMYB74c (myeloblastosis 74c), GbPIN2 (PIN-FORMED 2) associated with vascular development regulation, and GbWRKY1 (WRKYGOK 1), GbbHLH12a (basic helix-loop-helix 12a), and GbJAZ4 (jasmonate zim-domain 4) potentially involved in the formation of secretory cavities. Moreover, we found that flavonoid accumulation in mature embryos could enhance postgerminative growth and seedling establishment in harsh environments. Our 3D spatial reconstruction technique combined with multiomics analysis opens avenues for investigating developmental architecture and molecular mechanisms during embryogenesis and lays the foundation for evolutionary studies of embryo development and maturation.


Assuntos
Ginkgo biloba , Sementes , Ginkgo biloba/genética , Ginkgo biloba/embriologia , Sementes/genética , Sementes/crescimento & desenvolvimento , Imageamento Tridimensional/métodos , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Microtomografia por Raio-X , Cotilédone/genética , Multiômica
5.
Nature ; 574(7778): 394-398, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31619792

RESUMO

Inorganic materials have essential roles in society, including in building construction, optical devices, mechanical engineering and as biomaterials1-4. However, the manufacture of inorganic materials is limited by classical crystallization5, which often produces powders rather than monoliths with continuous structures. Several precursors that enable non-classical crystallization-such as pre-nucleation clusters6-8, dense liquid droplets9,10, polymer-induced liquid precursor phases11-13 and nanoparticles14-have been proposed to improve the construction of inorganic materials, but the large-scale application of these precursors in monolith preparations is limited by availability and by practical considerations. Inspired by the processability of polymeric materials that can be manufactured by crosslinking monomers or oligomers15, here we demonstrate the construction of continuously structured inorganic materials by crosslinking ionic oligomers. Using calcium carbonate as a model, we obtain a large quantity of its oligomers (CaCO3)n with controllable molecular weights, in which triethylamine acts as a capping agent to stabilize the oligomers. The removal of triethylamine initiates crosslinking of the (CaCO3)n oligomers, and thus the rapid construction of pure monolithic calcium carbonate and even single crystals with a continuous internal structure. The fluid-like behaviour of the oligomer precursor enables it to be readily processed or moulded into shapes, even for materials with structural complexity and variable morphologies. The material construction strategy that we introduce here arises from a fusion of classic inorganic and polymer chemistry, and uses the same cross-linking process for the manufacture the materials.


Assuntos
Carbonato de Cálcio/química , Química Inorgânica , Ciência dos Materiais/métodos , Polímeros/química
6.
Nano Lett ; 24(11): 3299-3306, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38442266

RESUMO

Cesium lead halide nanostructures have highly tunable optical and optoelectronic properties. Establishing precise control in forming perovskite single-crystal nanostructures is key to unlocking the full potential of these materials. However, studying the growth kinetics of colloidal cesium lead halides is challenging due to their sensitivity to light, electron beam, and environmental factors like humidity. In this study, in situ observations of CsPbBr3-particle dynamics were made possible through extremely low dose liquid cell transmission electron microscopy, showing that oriented attachment is the dominant pathway for the growth of single-crystal CsPbBr3 architectures from primary nanocubes. In addition, oriented assembly and fusion of ligand-stabilized cubic CsPbBr3 nanocrystals are promoted by electron beam irradiation or introduction of polar additives that both induce partial desorption of the original ligands and polarize the nanocube surfaces. These findings advance our understanding of cesium lead halide growth mechanisms, aiding the controlled synthesis of other perovskite nanostructures.

7.
Plant Cell Environ ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39254418

RESUMO

Old trees are remarkable for their ability to endure for centuries or even millennia, acting as recordkeepers of historical climate and custodians of genetic diversity. The secret to their longevity has long been a subject of fascination. Despite the challenges associated with studying old trees, such as massive size, slow growth rate, long lifespan and often remote habitat, accumulating studies have investigated the mechanisms underlying tree aging and longevity over the past decade. The recent publication of high-quality genomes of long-lived tree species, coupled with research on stem cell function and secondary metabolites in longevity, has brought us closer to unlocking the secrets of arboreal longevity. This review provides an overview of the global distribution of old trees and examines the environmental and anthropogenic factors that shape their presence. We summarize the contributions of physiological characteristics, stem cell activity, and immune system responses to their extraordinary longevity. We also explore the genetic and epigenetic 'longevity code', which consists of resistance and defense genes, DNA repair genes and patterns of DNA methylation modification. Further, we highlight key areas for future research that could enhance our understanding of the mechanisms underlying tree longevity.

8.
Plant Cell Environ ; 2024 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-39497283

RESUMO

Microplastics/nanoplastics are a top global environmental concern and have stimulated surging research into plant-nanoplastic interactions. Previous studies have examined the responses of plants to nanoplastic stress at various levels. Plant-specialized (secondary) metabolites play crucial roles in plant responses to environmental stress, whereas their roles in response to nanoplastic stress remain unknown. Here, we systematically examined the physiological and biochemical responses of Ginkgo biloba, a species with robust metabolite-driven defenses, to polystyrene nanoplastics (PSNPs). PSNPs negatively affected seedling growth and induced phytotoxicity, oxidative stress, and nuclear damage. Notably, PSNPs caused significant flavonoid accumulation, which enhances plant tolerance and detoxification against PSNP stress. To determine whether this finding is universal in plants, we subjected Arabidopsis, poplar, and tomato to PSNP stress and verified the common response of enhanced flavonoids across these species. To further confirm the role of flavonoids, we employed genetic transformation and staining techniques, validating the importance of flavonoids in mitigating excessive oxidative stress induced by NPs. Matrix analysis of transgenic plants with enhanced flavonoids further demonstrated altered downstream pathways, allocating more energy towards resilience against nanoplastic stress. Collectively, our results reveal the flavonoid multifaceted roles in enhancing plant resilience to nanoplastic stress, providing new knowledge about plant responses to nanoplastic contamination.

9.
J Exp Bot ; 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39470408

RESUMO

Flavonols are important secondary metabolites that enable plants to resist environmental stresses. Although MYB regulation of flavonol biosynthesis has been well studied, the lncRNA-MYB networks involved in regulating flavonol biosynthesis remain unknown. Ginkgo biloba is rich in flavonols, which are the most important medicinal components. Based on multi-omics data and phylogenetic trees, we identified GbMYB11 as a potential key transcription factor regulating flavonol biosynthesis. Overexpression and VIGS experiments confirmed that GbMYB11 acts as a pivotal positive regulator in flavonol biosynthesis. In the transcriptome of calli overexpressing GbMYB11, we identified significant upregulation of GbF3'H and GbFLS in the flavonol biosynthetic pathway. Yeast one-hybrid and dual-luciferase assays demonstrated that GbMYB11 enhances the expression of GbF3'H and GbFLS by binding to their promoters. Interestingly, we identified LncNAT11, an antisense lncRNA complement to GbMYB11, which negatively regulates flavonol biosynthesis by repressing the expression of GbMYB11. Consequently, we established the LncNAT11-GbMYB11-GbF3'H/GbFLS module as a critical regulator of flavonol biosynthesis in G. biloba, and further elucidated that this module can mitigate the accumulation of reactive oxygen species by modulating flavonol biosynthesis during salt stress. These findings unveil a novel mechanism underlying flavonol biosynthesis and a lncRNA-MYB mediated salt stress tolerance strategy in plants.

10.
Chemistry ; : e202402677, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158858

RESUMO

In this work, we developed a visible-light-driven method for the selective synthesis of amides and N-acylureas from carboxylic acids and thioureas. This protocol was featured as avoidance of additional oxidants and transition metal catalysts, simple manipulations, low cost, broad substrate scope, and good functional group tolerance. As only oxygen serves as the oxidation reagent, this method provides a promising synthesis candidate for the formation of N-aryl amides and N-acylureas, including late-stage functionalization of complex pharmaceutical molecules and biologically active molecules.

11.
BMC Cancer ; 24(1): 611, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773399

RESUMO

RNA interactomes and their diversified functionalities have recently benefited from critical methodological advances leading to a paradigm shift from a conventional conception on the regulatory roles of RNA in pathogenesis. However, the dynamic RNA interactomes in adenoma-carcinoma sequence of human CRC remain unexplored. The coexistence of adenoma, cancer, and normal tissues in colorectal cancer (CRC) patients provides an appropriate model to address this issue. Here, we adopted an RNA in situ conformation sequencing technology for mapping RNA-RNA interactions in CRC patients. We observed large-scale paired RNA counts and identified some unique RNA complexes including multiple partners RNAs, single partner RNAs, non-overlapping single partner RNAs. We focused on the antisense RNA OIP5-AS1 and found that OIP5-AS1 could sponge different miRNA to regulate the production of metabolites including pyruvate, alanine and lactic acid. Our findings provide novel perspectives in CRC pathogenesis and suggest metabolic reprogramming of pyruvate for the early diagnosis and treatment of CRC.


Assuntos
Adenoma , Neoplasias Colorretais , MicroRNAs , Ácido Pirúvico , RNA Longo não Codificante , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Ácido Pirúvico/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Regulação Neoplásica da Expressão Gênica , Reprogramação Metabólica
12.
Cell Commun Signal ; 22(1): 460, 2024 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-39342195

RESUMO

Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1-2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15-20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10-40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.


Assuntos
Carcinoma Neuroendócrino , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais
13.
Langmuir ; 40(8): 4350-4360, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38364791

RESUMO

Ceria nanomaterials with facile CeIII/IV redox behavior are used in sensing, catalytic, and therapeutic applications, where inclusion of CeIII has been correlated with reactivity. Understanding assembly pathways of CeO2 nanoparticles (NC-CeO2) in water has been challenged by "blind" synthesis, including rapid assembly/precipitation promoted by heat or strong base. Here, we identify a layered phase denoted Ce-I with a proposed formula CeIV(OH)3(NO3)·xH2O (x ≈ 2.5), obtained by adding electrolytes to aqueous cerium ammonium nitrate (CAN) to force precipitation. Ce-I represents intermediate hydrolysis species between dissolved CAN and NC-CeO2, where CAN is a commonly used CeIV compound that exhibits unusual aqueous and organic solubility. Ce-I features Ce-(OH)2-Ce units, representing the first step of hydrolysis toward NC-CeO2 formation, challenging prior assertions about CeIV hydrolysis. Structure/composition of poorly crystalline Ce-I was corroborated by a pair distribution function, Ce-L3 XAS (X-ray absorption spectroscopy), compositional analysis, and 17O nuclear magnetic resonance spectroscopy. Formation of Ce-I and its transformation to NC-CeO2 is documented in solution by small-angle X-ray scattering (SAXS) and in the solid-state by transmission electron microscopy (TEM) and powder X-ray diffraction. Morphologies identified by TEM support form factor models for SAXS analysis, evidencing the incipient assembly of Ce-I. Finally, two morphologies of NC-CeO2 are identified. Sequentially, spherical NC-CeO2 particles coexist with Ce-I, and asymmetric NC-CeO2 with up to 35% CeIII forms at the expense of Ce-I, suggesting direct replacement.

14.
Nano Lett ; 23(10): 4290-4297, 2023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-37141413

RESUMO

Supramolecular structures of matrix proteins in mineralizing tissues are known to direct the crystallization of inorganic materials. Here we demonstrate how such structures can be synthetically directed into predetermined patterns for which functionality is maintained. The study employs block copolymer lamellar patterns with alternating hydrophilic and hydrophobic regions to direct the assembly of amelogenin-derived peptide nanoribbons that template calcium phosphate nucleation by creating a low-energy interface. Results show that the patterned nanoribbons retain their ß-sheet structure and function and direct the formation of filamentous and plate-shaped calcium phosphate with high fidelity, where the phase, amorphous or crystalline, depends on the choice of mineral precursor and the fidelity depends on peptide sequence. The common ability of supramolecular systems to assemble on surfaces with appropriate chemistry combined with the tendency of many templates to mineralize multiple inorganic materials implies this approach defines a general platform for bottom-up-patterning of hybrid organic-inorganic materials.


Assuntos
Biomimética , Nanotubos de Carbono , Polímeros/química , Minerais , Fosfatos de Cálcio/química , Peptídeos/química
15.
Int J Mol Sci ; 25(17)2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39273532

RESUMO

Ginkgo biloba is a famous economic tree. Ginkgo leaves have been utilized as raw materials for medicines and health products due to their rich active ingredient composition, especially flavonoids. Since the routine measurement of total flavones is time-consuming and destructive, rapid, non-destructive detection of total flavones in ginkgo leaves is of significant importance to producers and consumers. Hyperspectral imaging technology is a rapid and non-destructive technique for determining the total flavonoid content. In this study, we discuss five modeling methods, and three spectral preprocessing methods are discussed. Bayesian Ridge (BR) and multiplicative scatter correction (MCS) were selected as the best model and the best pretreatment method, respectively. The spectral prediction results based on the BR + MCS treatment were very accurate (RTest2 = 0.87; RMSETest = 1.03 mg/g), showing a high correlation with the analytical measurements. In addition, we also found that the more and deeper the leaf cracks, the higher the flavonoid content, which helps to evaluate leaf quality more quickly and easily. In short, hyperspectral imaging is an effective technique for rapid and accurate determination of total flavonoids in ginkgo leaves and has great potential for developing an online quality detection system for ginkgo leaves.


Assuntos
Flavonoides , Ginkgo biloba , Folhas de Planta , Ginkgo biloba/química , Folhas de Planta/química , Flavonoides/análise , Aprendizado Profundo , Imageamento Hiperespectral/métodos , Extratos Vegetais/química , Extratos Vegetais/análise , Teorema de Bayes
16.
Molecules ; 29(4)2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38398631

RESUMO

Aqueous zinc ion batteries (AZIBs) have emerged as a promising battery technology due to their excellent safety, high capacity, low cost, and eco-friendliness. However, the cycle life of AZIBs is limited by severe side reactions and zinc dendrite growth on the zinc electrode surface, hindering large-scale application. Here, an electrolyte optimization strategy utilizing the simplest dipeptide glycylglycine (Gly-Gly) additive is first proposed. Theoretical calculations and spectral analysis revealed that, due to the strong interaction between the amino group and Zn atoms, Gly-Gly preferentially adsorbs on zinc's surface, constructing a stable and adaptive interfacial layer that inhibits zinc side reactions and dendrite growth. Furthermore, Gly-Gly can regulate zinc ion solvation, leading to a deposition mode shift from dendritic to lamellar and limiting two-dimensional dendrite diffusion. The symmetric cell with the addition of a 20 g/L Gly-Gly additive exhibits a cycle life of up to 1100 h. Under a high current density of 10 mA cm-2, a cycle life of 750 cycles further demonstrates the reliable adaptability of the interfacial layer. This work highlights the potential of Gly-Gly as a promising solution for improving the performance of AZIBs.

17.
Breast Cancer Res ; 25(1): 59, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37254190

RESUMO

Metastasis accounts for most cancer-associated deaths; yet, this complex process remains poorly understood, particularly the relationship between distant metastasis and primary site-derived cells. Here, we modified the classical MMTV-PyMT breast carcinoma model to trace the fate of mammary-derived carcinoma cells. We show that within the lung, when the metastatic breast carcinoma cells are conditionally depleted, transformed lung epithelial cells generate new metastases. Metastatic breast carcinoma cells transmit H19 long noncoding (lnc) RNA to lung epithelial cells through exosomes. SF3B1 bearing mutations at arginine-625 alternatively splices H19 lncRNA in lung epithelial cells, which selectively acts like a molecular sponge to sequester let-7a and induces Myc upregulation. Under the conditional elimination of primary site-derived breast carcinoma cells, lung malignant cells expressing the mutated SF3B1 splice variant dominate the newly created tumors. Our study suggests that these new carcinoma cells originating from within the colonized organ can replace the primary site-derived malignant cells whenever their expansion is abrogated using an inducible diphtheria toxin receptor in our designed system. These findings should call for a better understanding of metastatic tumors with the specific origin during cancer metastasis.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Neoplasias Mamárias Animais , RNA Longo não Codificante , Animais , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Processamento Alternativo , Mama/patologia , Pulmão/patologia , Neoplasias Mamárias Animais/patologia , Neoplasias Pulmonares/secundário , Fatores de Transcrição/genética , Linhagem Celular Tumoral
18.
J Med Virol ; 95(1): e28253, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36286245

RESUMO

Cytosolic recognition of microbial DNA in macrophages results in the activation of the interferon (IFN)-dependent antiviral innate immunity. Here, we examined whether activating DNA sensors in peripheral blood monocyte-derived macrophages (MDMs) can inhibit human immunodeficiency virus (HIV). We observed that the stimulation of MDMs with poly(dA:dT) or poly(dG:dC) (synthetic ligands for the DNA sensors) inhibited HIV infection and replication. MDMs treated with poly(dA:dT) or poly(dG:dC) expressed higher levels of both type I and type III IFNs than untreated cells. Activation of the DNA sensors in MDMs also induced the expression of the multiple intracellular anti-HIV factors, including IFN-stimulated genes (ISGs: ISG15, ISG56, Viperin, OAS2, GBP5, MxB, and Tetherin) and the HIV restriction microRNAs (miR-29c, miR-138, miR-146a, miR-155, miR-198, and miR-223). In addition, the DNA sensor activation of MDM upregulated the expression of the CC chemokines (RANTES, MIP-1α, MIP-1ß), the ligands for HIV entry coreceptor CCR5. These observations indicate that the cytosolic DNA sensors have a protective role in the macrophage intracellular immunity against HIV and that targeting the DNA sensors has therapeutic potential for immune activation-based anti-HIV treatment.


Assuntos
Infecções por HIV , HIV-1 , MicroRNAs , Humanos , Infecções por HIV/metabolismo , HIV-1/fisiologia , Células Cultivadas , Macrófagos , MicroRNAs/genética , MicroRNAs/metabolismo , DNA/metabolismo , Replicação Viral
19.
J Med Virol ; 95(11): e29217, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37933090

RESUMO

As a key immune cell in the brain, microglia are essential for protecting the central nervous system (CNS) from viral infections, including HIV. Microglia possess functional Toll-like receptor 3 (TLR3), a key viral sensor for activating interferon (IFN) signaling pathway-mediated antiviral immunity. We, therefore, studied the effect of poly (I:C), a synthetic ligand of TLR3, on the activation of the intracellular innate immunity against HIV in human iPSC-derived microglia (iMg). We found that poly (I:C) treatment of iMg effectively inhibits HIV infection/replication at both mRNA and protein levels. Investigations of the mechanisms revealed that TLR3 activation of iMg by poly (I:C) induced the expression of both type I and type III IFNs. Compared with untreated cells, the poly (I:C)-treated iMg expressed significantly higher levels of IFN-stimulated genes (ISGs) with known anti-HIV activities (ISG15, MxB, Viperin, MxA, and OAS-1). In addition, TLR3 activation elicited the expression of the HIV entry coreceptor CCR5 ligands (CC chemokines) in iMg. Furthermore, the transcriptional profile analysis showed that poly (I:C)-treated cells had the upregulated IFN signaling genes (ISG15, ISG20, IFITM1, IFITM2, IFITM3, IFITM10, APOBEC3A, OAS-2, MxA, and MxB) and the increased CC chemokine signaling genes (CCL1, CCL2, CCL3, CCL4, and CCL15). These observations indicate that TLR3 is a potential therapy target for activating the intracellular innate immunity against HIV infection/replication in human microglial cells. Therefore, further studies with animal models and clinical specimens are necessary to determine the role of TLR3 activation-driven antiviral response in the control and elimination of HIV in infected host cells.


Assuntos
Infecções por HIV , Células-Tronco Pluripotentes Induzidas , Microglia , Receptor 3 Toll-Like , Humanos , Células Cultivadas , Imunidade Inata , Microglia/virologia , Poli I-C/farmacologia , Receptor 3 Toll-Like/genética
20.
Opt Express ; 31(11): 17226-17234, 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37381462

RESUMO

We propose a simulation method for a multireflector terahertz imaging system. The description and verification of the method are based on an existing active bifocal terahertz imaging system at 0.22 THz. Using the phase conversion factor and angular spectrum propagation, the computation of the incident and received fields requires only a simple matrix operation. The phase angle is used to calculate the ray tracking direction, and the total optical path is used to calculate the scattering field of defective foams. Compared with the measurements and simulations of aluminum disks and defective foams, the validity of the simulation method is confirmed in the field of view of 50 cm × 90 cm at 8 m. This work aims to develop better imaging systems by predicting their imaging behavior for different targets before manufacturing.

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