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1.
iScience ; 24(11): 103243, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34746706

RESUMO

Prostaglandin E2 (PGE2) has recently been recognized to play a role in immune regulation and tissue regeneration. However, the short half-life of PGE2 limits its clinical application. Improving the delivery of PGE2 specifically to the target organ with a prolonged release method is highly desirable. Taking advantage of the adequate space and proximity of the renal parenchyma, renal subcapsular delivery allows minimally invasive and effective delivery to the entire kidney. Here, we report that by covalently cross-linking it to a collagen matrix, PGE2 exhibits an adequate long-term presence in the kidney with extensive intraparenchymal penetration through renal subcapsular delivery and significantly improves kidney function. Sox9 cell lineage tracing with intravital microscopy revealed that PGE2 could activate the endogenous renal progenitor Sox9+ cells through the Yap signaling pathway. Our results highlight the prospects of utilizing renal subcapsular-based drug delivery and facilitate new applications of PGE2-releasing matrices for regenerative therapy.

2.
Adv Mater ; : e2105879, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34632646

RESUMO

Moiré superlattices of 2D materials with a small twist angle are thought to exhibit appreciable flexoelectric effect, though unambiguous confirmation of their flexoelectricity is challenging due to artifacts associated with commonly used piezoresponse force microscopy (PFM). For example, unexpectedly small phase contrast (≈8°) between opposite flexoelectric polarizations is reported in twisted bilayer graphene (tBG), though theoretically predicted value is 180°. Here a methodology is developed to extract intrinsic moiré flexoelectricity using twisted double bilayer graphene (tDBG) as a model system, probed by lateral PFM. For small twist angle samples, it is found that a vectorial decomposition is essential to recover the small intrinsic flexoelectric response at domain walls from a large background signal. The obtained threefold symmetry of commensurate domains with significant flexoelectric response at domain walls is fully consistent with the theoretical calculations. Incommensurate domains in tDBG with relatively large twist angles can also be observed by this technique. A general strategy is provided here for unraveling intrinsic flexoelectricity in van der Waals moiré superlattices while providing insights into engineered symmetry breaking in centrosymmetric materials.

3.
Nat Commun ; 12(1): 6226, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34711821

RESUMO

The bulk morphology of the active layer of organic solar cells (OSCs) is known to be crucial to the device performance. The thin film device structure breaks the symmetry into the in-plane direction and out-of-plane direction with respect to the substrate, leading to an intrinsic anisotropy in the bulk morphology. However, the characterization of out-of-plane nanomorphology within the active layer remains a grand challenge. Here, we utilized an X-ray scattering technique, Grazing-incident Transmission Small-angle X-ray Scattering (GTSAXS), to uncover this new morphology dimension. This technique was implemented on the model systems based on fullerene derivative (P3HT:PC71BM) and non-fullerene systems (PBDBT:ITIC, PM6:Y6), which demonstrated the successful extraction of the quantitative out-of-plane acceptor domain size of OSC systems. The detected in-plane and out-of-plane domain sizes show strong correlations with the device performance, particularly in terms of exciton dissociation and charge transfer. With the help of GTSAXS, one could obtain a more fundamental perception about the three-dimensional nanomorphology and new angles for morphology control strategies towards highly efficient photovoltaic devices.

4.
J Int Med Res ; 49(10): 3000605211053233, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34704484

RESUMO

OBJECTIVE: This meta-analysis was conducted to investigate the relationship between the interleukin (IL)-17A rs2275913 polymorphism and rheumatoid arthritis (RA) susceptibility. METHODS: Eligible studies were retrieved from PubMed, Embase, and Web of Science. The fixed- or random-effects model was used to calculate the pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) on the basis of heterogeneity. RESULTS: Overall, 11 studies containing 4019 RA patients and 4137 controls were included in this meta-analysis. The results suggested a significant association between the IL-17A rs2275913 polymorphism and RA susceptibility in the overall population (allelic model A vs. G: OR = 0.89, 95%CI: 0.83-0.95; heterozygote model GA vs. GG: OR = 0.87, 95%CI: 0.78-0.96; homozygote model AA vs. GG: OR = 0.82, 95%CI: 0.71-0.96; dominant model GA + AA vs. GG: OR = 0.86, 95%CI: 0.78-0.94). In the subgroup analyses, the IL-17A rs2275913 polymorphism was significantly associated with RA risk in Europeans (allelic model A vs. G: OR = 0.87, 95%CI: 0.78-0.97; heterozygote model GA vs. GG: OR = 0.79, 95%CI: 0.68-0.93; dominant model GA + AA vs. GG: OR = 0.79, 95%CI: 0.68-0.92), but not in Africans or Americans. CONCLUSION: This study suggests that the IL-17A rs2275913 polymorphism is significantly associated with RA susceptibility in Europeans.INPLASY registration number: INPLASY202170056.


Assuntos
Artrite Reumatoide , Interleucina-17 , Artrite Reumatoide/genética , Predisposição Genética para Doença , Humanos , Interleucina-17/genética , Interleucinas , Polimorfismo de Nucleotídeo Único/genética
5.
Carbohydr Polym ; 273: 118496, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34560937

RESUMO

A homogeneous polysaccharide, EJP90-1, was isolated from the leaves of E. japonica by hot water extraction in this study. EJP90-1 (7702 Da) was a heteropolysaccharide mainly consisting of →5)-linked-α-L-Araf-(1→, →4)-linked-ß-D-Manp-(1→, →2,4)-linked-α-L-Rhap-(1→, →4)-linked-α-D-Xylp-(1→, →4)-linked-ß-D-Galp-(1→, →2)-linked-ß-D-Galp-(1→, →6)-linked-ß-D-Glcp-(1→, α-D-Glcp-(4→, and t-linked-α-L-Araf. EJP90-1 was found to show moderate anti-tumor activity at the cellular level. In order to improve the anti-tumor activity and the potential applications of EJP90-1, a typical sodium selenite-nitric acid (Na2SeO3-HNO3) modification on EJP90-1 was carried out. X-ray photoelectron spectroscopy (XPS) and energy dispersive spectrometer (EDS) analysis confirmed that Se was successfully introduced into the polymer chain of EJP90-1. The subsequent in vitro cytotoxicity evaluation showed the selenylation modification derivative (EJP90-1-Se) possessed significant antiproliferative activity against cancer cells (HepG2 and A549 cells) through inducing cell apoptosis. The anti-tumor activity of EJP90-1-Se was further confirmed by zebrafish models, which inhibited the proliferation and migration of HepG2 cells and the angiogenesis.

6.
Autophagy ; : 1-16, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520306

RESUMO

Mutations in the macroautophagy/autophagy gene EPG5 are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that epg5-/- mice exhibit hyperinflammation in the lungs mediated by IL1B/IL-1ß and TNF/TNFα, resulting in resistance to influenza. Here, we find that disruption of Epg5 results in protection against multiple enteric viruses including norovirus and rotavirus. Gene expression analysis reveals IFNL/IFN-λ responsive genes as a key alteration. Further, mice lacking Epg5 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate Epg5-associated inflammation of both the intestine and lung is microbiota-independent. Genetic studies support IFNL signaling as the primary mediator of resistance to enteric viruses, but not of microbial dysbiosis, in epg5-/- mice. This study unveils an important role, unexpectedly independent of the microbiota, for autophagy gene Epg5 in host organism protection by modulating intestinal IFNL responses.Abbreviations: CTNNB1: catenin (cadherin associated protein), beta 1; DAPI: 4',6-diamidino-2-phenylindole; EPG5: ectopic P-granules autophagy protein 5 homolog (C. elegans); FT: fecal transplant; IFI44: interferon-induced protein 44; IFIT1: interferon-induced protein with tetratricopeptide repeats 1; IFNG/IFN-γ: interferon gamma; IFNL/IFN-λ: interferon lambda; IFNLR1: interferon lambda receptor 1; IL1B/IL-1ß: interleukin 1 beta; ISG: interferon stimulated gene; GF: germ-free; LEfSe: linear discriminant analysis effect size; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MNoV: murine norovirus; MX2: MX dynamin-like GTPase 2; OAS1A: 2'-5' oligoadenylate synthetase 1A; RV: rotavirus; SPF: specific-pathogen free; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1; TNF/TNFα: tumor necrosis factor.

7.
Carbohydr Polym ; 270: 118365, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34364610

RESUMO

In this study, an inulin fructan (TMP50-2) with moderate anti-tumor activity was obtained from dandelion. To further improve the anti-tumor activity of TMP50-2, a monodisperse and stable spherical nanoparticle (Tw-TMP-SeNP, 50 nm) was fabricated. Physico-chemical analysis revealed that TMP50-2 and Tween 80 were tightly wrapped on the surface of SeNPs by forming CO⋯Se bonds or through hydrogen bonding interaction (OH⋯Se). In vitro anti-tumor assay showed that Tw-TMP-SeNP treatment could significantly inhibit the proliferation of cancer cells (HepG2, A549, and HeLa) in a dose-dependent manner, while HepG2 cells were more susceptible to Tw-TMP-SeNP with an IC50 value of 46.8 µg/mL. The apoptosis induction of HepG2 cells by Tw-TMP-SeNP was evidenced by increasing the proportion of apoptotic cells ranging from 12.5% to 27.4%. Furthermore, in vivo zebrafish model confirmed the anti-tumor activity of Tw-TMP-SeNP by inhibiting the proliferation and migration of tumor cells as well as the angiogenesis of zebrafish embryos.

8.
Curr Med Chem ; 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34365944

RESUMO

The complexity of tumor microenvironment and the diversity of tumors seriously affect the therapeutic effect, the focus, therefore, has gradually been shifted from monotherapy to combination therapy in clinical research in order to improve the curative effect. The synergistic enhancement interactions among multiple monotherapies majorly contribute to the birth of the multi-mode cooperative therapy, whose effect of the treatment is clearly stronger than that of any single therapy. In addition, the accurate diagnosis of the tumour location is also crucial to the treatment. Bismuth-based nanomaterials (NMs) hold great properties as promising theranostic platforms based on their many unique features that include low toxicity, excellent photothermal conversion efficiency as well as high ability of X-ray computed tomography imaging and photoacoustic imaging. In this review, we will introduce briefly the main features of tumor microenvironment first and its effect on the mechanism of nanomedicine actions and present the recent advances of bismuth-based NMs for diagnosis and photothermal therapy-based combined therapies using bismuth-based NMs are presented, which may provide a new way for overcoming drug resistance and hypoxia. At the end, further challenges and outlooks regarding this promising field are discussed accompanied with some design tips for bismuth-based NMs, hoping to provide researchers some inspirations to design safe and effective nanotherapeutic agents for the clinical treatments of cancers.

9.
Nucleic Acids Res ; 49(16): 9132-9153, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34390351

RESUMO

Transposable elements (TEs) occupy nearly 40% of mammalian genomes and, whilst most are fragmentary and no longer capable of transposition, they can nevertheless contribute to cell function. TEs within genes transcribed by RNA polymerase II can be copied as parts of primary transcripts; however, their full contribution to mature transcript sequences remains unresolved. Here, using long and short read (LR and SR) RNA sequencing data, we show that 26% of coding and 65% of noncoding transcripts in human pluripotent stem cells (hPSCs) contain TE-derived sequences. Different TE families are incorporated into RNAs in unique patterns, with consequences to transcript structure and function. The presence of TE sequences within a transcript is correlated with TE-type specific changes in its subcellular distribution, alterations in steady-state levels and half-life, and differential association with RNA Binding Proteins (RBPs). We identify hPSC-specific incorporation of endogenous retroviruses (ERVs) and LINE:L1 into protein-coding mRNAs, which generate TE sequence-derived peptides. Finally, single cell RNA-seq reveals that hPSCs express ERV-containing transcripts, whilst differentiating subpopulations lack ERVs and express SINE and LINE-containing transcripts. Overall, our comprehensive analysis demonstrates that the incorporation of TE sequences into the RNAs of hPSCs is more widespread and has a greater impact than previously appreciated.


Assuntos
Retrovirus Endógenos/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Células-Tronco Pluripotentes/metabolismo , Transcriptoma , Linhagem Celular , Humanos , RNA não Traduzido/genética , Proteínas de Ligação a RNA/metabolismo
10.
Nat Commun ; 12(1): 4727, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354061

RESUMO

Flat band moiré superlattices have recently emerged as unique platforms for investigating the interplay between strong electronic correlations, nontrivial band topology, and multiple isospin 'flavor' symmetries. Twisted monolayer-bilayer graphene (tMBG) is an especially rich system owing to its low crystal symmetry and the tunability of its bandwidth and topology with an external electric field. Here, we find that orbital magnetism is abundant within the correlated phase diagram of tMBG, giving rise to the anomalous Hall effect in correlated metallic states nearby most odd integer fillings of the flat conduction band, as well as correlated Chern insulator states stabilized in an external magnetic field. The behavior of the states at zero field appears to be inconsistent with simple spin and valley polarization for the specific range of twist angles we investigate, and instead may plausibly result from an intervalley coherent (IVC) state with an order parameter that breaks time reversal symmetry. The application of a magnetic field further tunes the competition between correlated states, in some cases driving first-order topological phase transitions. Our results underscore the rich interplay between closely competing correlated ground states in tMBG, with possible implications for probing exotic IVC ordering.

11.
Small ; 17(34): e2101015, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34263544

RESUMO

Solid tumors possess a unique internal environment with high-level thiols (mainly glutathione), over-expressed H2 O2 , and low oxygen partial pressure, which severely restrict the radiotherapy (RT) efficacy. To overcome the imperfections of RT alone, there is vital to design a multifunctional radiosensitizer that simultaneously achieves multimodal therapy and tumor microenvironment (TME) regulation. Bismuth (Bi)-based nanospheres are wrapped in the MnO2 layer to form core-shell-structured radiosensitizer (Bi@Mn) that can effectively load docetaxel (DTX). The solubility of Bi@Mn-DTX is further improved via folic acid-modified amphiphilic polyethylene glycol (PFA). Bi@Mn-DTX-PFA can specifically respond to the TME to realize multimodal therapy. Primarily, the outer MnO2 layer responds with H2 O2 and glutathione to release oxygen and generate •OH, thereby alleviating hypoxia and achieving chemodynamic therapy (CDT). Afterward, the strong coordination between Bi3+ and deprotonated thiol groups in glutathione allows the mesoporous Bi-containing core bonding with glutathione to form a water-soluble complex. These actions conduce Bi@Mn-DTX-PFA degradation, further releasing DTX to implement chemotherapy (CHT). In addition, the degradation in vivo and tumor enrichment of Bi@Mn-PFA are explored via T1 -weighted magnetic resonance and computed tomography imaging. The biodegradable composite Bi@Mn-DTX-PFA can simultaneously modulate the TME and achieve multimodal treatment (RT/CDT/CHT) for hypoxic tumors.


Assuntos
Neoplasias , Microambiente Tumoral , Bismuto , Humanos , Hipóxia , Manganês , Compostos de Manganês , Neoplasias/tratamento farmacológico , Óxidos
12.
Front Neurosci ; 15: 667329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113234

RESUMO

Purpose: This study aimed to evaluate short-term visual performance and optical quality of three different lenslet configurations on myopia control spectacle lenses. Materials and Methods: This study utilized a cross-over design. Distance visual acuity (VA) was measured in 50 myopic children; contrast sensitivity (CS) was measured in 36 myopic children. For each test, four spectacle lenses were evaluated in a random order: single-vision lens (SVL), lens with concentric rings of highly aspherical lenslets (HAL), lens with concentric rings of slightly aspherical lenslets (SAL), and lens with honeycomb configuration of spherical lenslets (HC). The modulation transfer function (MTF) and MTF area (MTFa) were used to determine optical quality. All tests were performed monocularly on the right eye with full correction. Results: HAL and SAL had larger MTFa than HC. VA in lenses with lenslets was significantly reduced compared to SVL (all p < 0.01). The reduction in VA was worse with HC than with SAL (p = 0.02) and HAL (p = 0.03); no effect of lenslet asphericity was found (p > 0.05). VA changes induced by lenslets showed no correlation with spherical equivalent refraction (all p > 0.05) and were weakly positively associated with age for SAL (r = 0.36, p = 0.01) and HC (r = 0.31, p = 0.03), but not for HAL (p = 0.30). The area under the log contrast sensitivity function (AULCSF) decreased with HAL and HC (all p < 0.001) in all illumination levels, and AULCSF with HAL was higher than that with HC in a photopic condition (1.17 ± 0.10 vs. 1.10 ± 0.13, p = 0.0004). The presence of lenslets did not affect CS at 3 cycles per degree (cpd) (p = 0.80). At 6 to 18 cpd, CS was significantly reduced by HAL and HC (all p < 0.05), but not SAL (p > 0.05) compared to SVL. At high spatial frequencies (>12 cpd) both SAL and HAL reduced CS significantly less than HC (all p < 0.01). Conclusion: Short-term visual performance was minimally impaired by looking through the lenslet structure of myopia control spectacle lenses. Concentric rings with aspherical lenslets had a significantly lower impact on both VA and CS than honeycomb configuration with spherical lenslets.

13.
Talanta ; 230: 122294, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33934766

RESUMO

The determination approaches of Fe (Ⅲ) in biological samples were developed by a novel water-soluble silicon nanoparticles (SiNPs). The SiNPs were synthesized by a facile microwave-assisted method, and simultaneously featured strong blue fluorescence (photoluminescence quantum yield: 25.2%), long lifetime (~13.29 ns) and good photo-stability. The fluorescence intensities of SiNPs were gradually quenched with Fe (Ⅲ) concentration increasing from 2.0 to 50 µmol/L. The detection limit of the established method was 0.56 µmol/L and the precision for eleven replicate detections of 20 µmol/L Fe (Ⅲ) was 3.2% (relative standard deviation, RSD). The spiked recoveries were 99.0%-104.5%. Results of the lifetime decay and cyclic voltammetry (CV) evidenced that the electron transfer was responsible for the fluorescence quenching mechanism of SiNPs and Fe (Ⅲ). Moreover, the SiNPs were successfully applied in the determination of Fe(Ⅲ) in different environmental waters and human serum. Finally, the resulting SiNPs exhibited the green fluorescence in HeLa cells as the optical probe.


Assuntos
Nanopartículas , Silício , Compostos Férricos , Células HeLa , Humanos , Espectrometria de Fluorescência
14.
Acta Biomater ; 129: 280-292, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34033970

RESUMO

Various physiological characteristics of the tumor microenvironment (TME), such as hypoxia, overexpression of glutathione (GSH) and hydrogen peroxide (H2O2), and mild acidity, can severely reduce the efficacy of many cancer therapies. Altering the redox balance of the TME and increasing oxidative stress can accordingly enhance the efficacy of tumor therapy. Herein, we developed a bismuth-based Cu2+-doped BiOCl nanotherapeutic platform, BCHN, able to self-supply H2O2 for TME-regulated chemodynamic therapy (CDT) combined with sensitized radiotherapy (RT). BCHN released H2O2 and consumed GSH to degrade the composite in the slightly acidic TME, and generated hydroxyl radicals (•OH) via a Fenton-like reaction catalyzed by copper ions, to achieve oxidative stress-enhanced CDT. The Fenton-like reaction also catalyzed H2O2 to produce O2 to relieve tumor hypoxia, and combined with the X-ray-blocking property of bismuth to realize TME-enhanced radiotherapy. Synergistic CDT/RT has previously been shown to effectively inhibit tumor cell proliferation and achieve effective tumor control. The current results demonstrated a highly efficient multifunctional bio-degradable nanoplatform for oncotherapy. STATEMENT OF SIGNIFICANCE: Tumor microenvironment-modulated synergy of radiotherapy and chemodynamic therapy is conducive to rapid tumor ablation. Based on this principle, we fabricated a biodegradable BiOCl-based nanocomposite, BCHN. By supplying H2O2, a Fenton-like reaction generated •OH and O2 catalyzed by copper ions, and consumed glutathione to biodegrade the composite. Overall, these actions increased tumor oxidative stress and realized the synergistic anti-tumor actions of chemodynamic therapy combined with bismuth-based sensitization radiotherapy. This strategy thus provides a unique approach to oncology therapy.


Assuntos
Peróxido de Hidrogênio , Microambiente Tumoral , Linhagem Celular Tumoral , Humanos , Hipóxia , Estresse Oxidativo
15.
Nat Commun ; 12(1): 2944, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011941

RESUMO

The ~2.22-2.06 Ga Lomagundi Event was the longest positive carbon isotope excursion in Earth's history and is commonly interpreted to reflect perturbations in continental weathering and the phosphorous cycle. Previous models have focused on mechanisms of increasing phosphorous solubilization during weathering without focusing on transport to the oceans and its dispersion in seawater. Building from new experimental results, here we report kaolinite readily absorbs phosphorous under acidic freshwater conditions, but quantitatively releases phosphorous under seawater conditions where it becomes bioavailable to phytoplankton. The strong likelihood of high weathering intensities and associated high kaolinite content in post-Great-Oxidation-Event paleosols suggests there would have been enhanced phosphorus shuttling from the continents into marine environments. A kaolinite phosphorous shuttle introduces the potential for nonlinearity in the fluxes of phosphorous to the oceans with increases in chemical weathering intensity.

16.
Int J Biol Macromol ; 183: 90-100, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33872613

RESUMO

A water-soluble polysaccharide identified here as ADP80-2 was acquired from Angelica dahurica. ADP80-2 was a gluco-arabinan composed of arabinose and a trace of glucose with a molecular weight of 9950 g/mol. The backbone of ADP80-2 comprised →5)-α-L-Araf-(1→, →3, 5)-α-L-Araf-(1→, →6)-α-D-Glcp-(1→, with a terminal branch α-L-Araf-(1 → residue. In terms of immunoregulatory activity, ADP80-2 can significantly promote the phagocytosis, the production of nitric oxide (NO), and the secretion of cytokines (IL-6, IL-1ß, and TNF-α) of macrophage. In addition to the cellular immunomodulatory activities, the chemokines related to immunoregulation were significantly increased in the zebrafish model after treated with ADP80-2. These biological results indicated that ADP80-2 with immunomodulatory effects was expected to be useful for the development of new immunomodulatory agents. Simultaneously, the discovery of ADP80-2 further revealed the chemical composition of A. dahurica used as a traditional Chinese medicine and spice.


Assuntos
Angelica , Fatores Imunológicos/farmacologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Angelica/química , Animais , Configuração de Carboidratos , Citocinas/metabolismo , Fatores Imunológicos/isolamento & purificação , Mediadores da Inflamação/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismo
17.
Mitochondrial DNA B Resour ; 6(3): 1118-1119, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33796760

RESUMO

This study describes the first sequencing of the complete mitochondrial genome of Schizothorax sinensis, a species of cyprinid snowtrout from the Jialing River and Fujiang River basins in China's Sichuan Province. The total length is 16,571 base pairs. Similar to most Schizothoracinae mitochondrial genomes, there are 37 genes including 13 protein coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. In addition, it contains a control region rich in A-T nucleotides. The overall nucleotide composition is 29.6% for A, 27.1% for C, 17.9% for G and 25.4% for T, and the percentage of GC content is 45.0%. Phylogenetic analysis suggested that Schizothorax sinensis and Schizothorax prenanti clustered together in a clade. This work provides additional molecular information for studying Schizothorax sinensis conservation genetics and evolutionary relationships.

19.
Mucosal Immunol ; 14(3): 751-761, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674763

RESUMO

Although they globally cause viral gastroenteritis in children, astroviruses are understudied due to the lack of well-defined animal models. While murine astroviruses (muAstVs) chronically infect immunodeficient mice, a culture system and understanding of their pathogenesis is lacking. Here, we describe a platform to cultivate muAstV using air-liquid interface (ALI) cultures derived from mouse enteroids, which support apical infection and release. Chronic muAstV infection occurs predominantly in the small intestine and correlates with higher interferon-lambda (IFN-λ) expression. MuAstV stimulates IFN-λ production in ALI, recapitulating our in vivo findings. We demonstrate that goblet cells and enterocytes are targets for chronic muAstV infection in vivo, and that infection is enhanced by parasite co-infection or type 2 cytokine signaling. Depletion of goblet cells from ALI limits muAstV infection in vitro. During chronic infection, muAstV stimulates IFN-λ production in infected cells and induces ISGs throughout the intestinal epithelium in an IFN-λ-receptor-dependent manner. Collectively, our study provides insights into the cellular tropism and innate immune responses to muAstV and establishes an enteroid-based culture system to propagate muAstV in vitro.

20.
PLoS Pathog ; 17(3): e1009402, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33705489

RESUMO

Interferons (IFNs) are key controllers of viral replication, with intact IFN responses suppressing virus growth and spread. Using the murine norovirus (MNoV) system, we show that IFNs exert selective pressure to limit the pathogenic evolutionary potential of this enteric virus. In animals lacking type I IFN signaling, the nonlethal MNoV strain CR6 rapidly acquired enhanced virulence via conversion of a single nucleotide. This nucleotide change resulted in amino acid substitution F514I in the viral capsid, which led to >10,000-fold higher replication in systemic organs including the brain. Pathogenicity was mediated by enhanced recruitment and infection of intestinal myeloid cells and increased extraintestinal dissemination of virus. Interestingly, the trade-off for this mutation was reduced fitness in an IFN-competent host, in which CR6 bearing F514I exhibited decreased intestinal replication and shedding. In an immunodeficient context, a spontaneous amino acid change can thus convert a relatively avirulent viral strain into a lethal pathogen.


Assuntos
Infecções por Caliciviridae/virologia , Proteínas do Capsídeo/genética , Norovirus/genética , Norovirus/patogenicidade , Virulência/genética , Animais , Infecções por Caliciviridae/genética , Infecções por Caliciviridae/imunologia , Aptidão Genética/genética , Imunidade Inata/imunologia , Camundongos , Norovirus/imunologia , Polimorfismo de Nucleotídeo Único , Virulência/imunologia , Replicação Viral
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