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Hot-carrier transistors are a class of devices that leverage the excess kinetic energy of carriers. Unlike regular transistors, which rely on steady-state carrier transport, hot-carrier transistors modulate carriers to high-energy states, resulting in enhanced device speed and functionality. These characteristics are essential for applications that demand rapid switching and high-frequency operations, such as advanced telecommunications and cutting-edge computing technologies1-5. However, the traditional mechanisms of hot-carrier generation are either carrier injection6-11 or acceleration12,13, which limit device performance in terms of power consumption and negative differential resistance14-17. Mixed-dimensional devices, which combine bulk and low-dimensional materials, can offer different mechanisms for hot-carrier generation by leveraging the diverse potential barriers formed by energy-band combinations18-21. Here we report a hot-emitter transistor based on double mixed-dimensional graphene/germanium Schottky junctions that uses stimulated emission of heated carriers to achieve a subthreshold swing lower than 1 millivolt per decade beyond the Boltzmann limit and a negative differential resistance with a peak-to-valley current ratio greater than 100 at room temperature. Multi-valued logic with a high inverter gain and reconfigurable logic states are further demonstrated. This work reports a multifunctional hot-emitter transistor with significant potential for low-power and negative-differential-resistance applications, marking a promising advancement for the post-Moore era.
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Calor , Transistores Electrónicos , Grafito/químicaRESUMEN
Deletion is a crucial type of genomic structural variation and is associated with numerous genetic diseases. The advent of third-generation sequencing technology has facilitated the analysis of complex genomic structures and the elucidation of the mechanisms underlying phenotypic changes and disease onset due to genomic variants. Importantly, it has introduced innovative perspectives for deletion variants calling. Here we propose a method named Dual Attention Structural Variation (DASV) to analyze deletion structural variations in sequencing data. DASV converts gene alignment information into images and integrates them with genomic sequencing data through a dual attention mechanism. Subsequently, it employs a multi-scale network to precisely identify deletion regions. Compared with four widely used genome structural variation calling tools: cuteSV, SVIM, Sniffles and PBSV, the results demonstrate that DASV consistently achieves a balance between precision and recall, enhancing the F1 score across various datasets. The source code is available at https://github.com/deconvolution-w/DASV.
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Secuenciación de Nucleótidos de Alto Rendimiento , Programas Informáticos , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Eliminación de Secuencia , Análisis de Secuencia de ADN/métodos , Algoritmos , Genómica/métodos , Biología Computacional/métodosRESUMEN
Understanding the factors underpinning device switching times is crucial for the implementation of organic electrochemical transistors in neuromorphic computing, bioelectronics and real-time sensing applications. Existing models of device operation cannot explain the experimental observations that turn-off times are generally much faster than turn-on times in accumulation mode organic electrochemical transistors. Here, using operando optical microscopy, we image the local doping level of the transistor channel and show that turn-on occurs in two stages-propagation of a doping front, followed by uniform doping-while turn-off occurs in one stage. We attribute the faster turn-off to a combination of engineering as well as physical and chemical factors including channel geometry, differences in doping and dedoping kinetics and the phenomena of carrier-density-dependent mobility. We show that ion transport limits the operation speed in our devices. Our study provides insights into the kinetics of organic electrochemical transistors and guidelines for engineering faster organic electrochemical transistors.
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BACKGROUND AND AIMS: Extracellular vesicles (EVs) secreted by cardiosphere-derived cells exert immunomodulatory effects through the transmission of small non-coding RNAs. METHODS: The mechanism and role of yREX3, a small Y RNA abundant in EVs in myocardial injury, was investigated. RESULTS: yREX3 attenuates cardiac ischaemic injury by selective DNA methylation. Synthetic yREX3 encapsulated in lipid nanoparticles triggers broad transcriptomic changes in macrophages, localizes to the nucleus, and mediates epigenetic silencing of protein interacting with C kinase-1 (Pick1) through methylation of upstream CpG sites. Moreover, yREX3 interacts with polypyrimidine tract binding protein 3 (PTBP3) to methylate the Pick1 gene locus in a DNA methyltransferase-dependent manner. Suppression of Pick1 in macrophages potentiates Smad3 signalling and enhances efferocytosis, minimizing heart necrosis in rats with myocardial infarction. Adoptive transfer of Pick1-deficient macrophages recapitulates the cardioprotective effects of yREX3 in vivo. CONCLUSIONS: These findings highlight the role of a small Y RNA mined from EVs with a novel gene-methylating mechanism.
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Vesículas Extracelulares , Macrófagos , Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Animales , Humanos , Metilación de ADN , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Infarto del Miocardio/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Ratas , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MasculinoRESUMEN
BACKGROUND: Hepatitis B virus (HBV) integrates into human chromosomes and can lead to genomic instability and hepatocarcinogenesis. Current tools for HBV integration site detection lack accuracy and stability. RESULTS: This study proposes a deep learning-based method, named ViroISDC, for detecting integration sites. ViroISDC generates corresponding grammar rules and encodes the characteristics of the language data to predict integration sites accurately. Compared with Lumpy, Pindel, Seeksv, and SurVirus, ViroISDC exhibits better overall performance and is less sensitive to sequencing depth and integration sequence length, displaying good reliability, stability, and generality. Further downstream analysis of integrated sites detected by ViroISDC reveals the integration patterns and features of HBV. It is observed that HBV integration exhibits specific chromosomal preferences and tends to integrate into cancerous tissue. Moreover, HBV integration frequency was higher in males than females, and high-frequency integration sites were more likely to be present on hepatocarcinogenesis- and anti-cancer-related genes, validating the reliability of the ViroISDC. CONCLUSIONS: ViroISDC pipeline exhibits superior precision, stability, and reliability across various datasets when compared to similar software. It is invaluable in exploring HBV infection in the human body, holding significant implications for the diagnosis, treatment, and prognosis assessment of HCC.
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Virus de la Hepatitis B , Integración Viral , Virus de la Hepatitis B/genética , Humanos , Integración Viral/genética , Programas Informáticos , Aprendizaje Profundo , Masculino , Femenino , Hepatitis B/genética , Hepatitis B/virología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Biología Computacional/métodosRESUMEN
Plant growth and development can be significantly impacted by drought stress. Plants will adjust the synthesis and accumulation of secondary metabolites to improve survival in times of water constraint. Simultaneously, drought stress can lead to modifications in the DNA methylation status of plants, and these modifications can directly impact gene expression and product synthesis by changing the DNA methylation status of functional genes involved in secondary metabolite synthesis. However, further research is needed to fully understand the extent to which DNA methylation modifies the content of secondary metabolites to mediate plants' responses to drought stress, as well as the underlying mechanisms involved. Our study found that in Eleutherococcus senticosus (E. senticosus), moderate water deprivation significantly decreased DNA methylation levels throughout the genome and at the promoters of EsFPS, EsSS, and EsSE. Transcription factors like EsMYB-r1, previously inhibited by DNA methylation, can re-bind to the EsFPS promotor region following DNA demethylation. This process promotes gene expression and, ultimately, saponin synthesis and accumulation. The increased saponin levels in E. senticosus acted as antioxidants, enhancing the plant's adaptability to drought stress.
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Eleutherococcus , Saponinas , Metilación de ADN , Eleutherococcus/genética , Eleutherococcus/metabolismo , Metabolismo Secundario , SequíasRESUMEN
BACKGROUND: ATP-binding cassette (ABC) transporter proteins constitute a plant gene superfamily crucial for growth, development, and responses to environmental stresses. Despite their identification in various plants like maize, rice, and Arabidopsis, little is known about the information on ABC transporters in pear. To investigate the functions of ABC transporters in pear development and abiotic stress response, we conducted an extensive analysis of ABC gene family in the pear genome. RESULTS: In this study, 177 ABC transporter genes were successfully identified in the pear genome, classified into seven subfamilies: 8 ABCAs, 40 ABCBs, 24 ABCCs, 8 ABCDs, 9 ABCEs, 8 ABCFs, and 80 ABCGs. Ten motifs were common among all ABC transporter proteins, while distinct motif structures were observed for each subfamily. Distribution analysis revealed 85 PbrABC transporter genes across 17 chromosomes, driven primarily by WGD and dispersed duplication. Cis-regulatory element analysis of PbrABC promoters indicated associations with phytohormones and stress responses. Tissue-specific expression profiles demonstrated varied expression levels across tissues, suggesting diverse functions in development. Furthermore, several PbrABC genes responded to abiotic stresses, with 82 genes sensitive to salt stress, including 40 upregulated and 23 downregulated genes. Additionally, 91 genes were responsive to drought stress, with 22 upregulated and 36 downregulated genes. These findings highlight the pivotal role of PbrABC genes in abiotic stress responses. CONCLUSION: This study provides evolutionary insights into PbrABC transporter genes, establishing a foundation for future research on their functions in pear. The identified motifs, distribution patterns, and stress-responsive expressions contribute to understanding the regulatory mechanisms of ABC transporters in pear. The observed tissue-specific expression profiles suggest diverse roles in developmental processes. Notably, the significant responses to salt and drought stress emphasize the importance of PbrABC genes in mediating adaptive responses. Overall, our study advances the understanding of PbrABC transporter genes in pear, opening avenues for further investigations in plant molecular biology and stress physiology.
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Transportadoras de Casetes de Unión a ATP , Pyrus , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Pyrus/genética , Proteínas de Transporte de Membrana/genética , Estrés Fisiológico/genética , Adenosina Trifosfato , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Familia de Multigenes , Regulación de la Expresión Génica de las PlantasRESUMEN
Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.
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Neoplasias de la Mama , Histona Demetilasas , Terapia Molecular Dirigida , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/genética , Biomarcadores de TumorRESUMEN
BACKGROUND: circular RNAs (circRNAs) have been reported to exert important effects in the progression of numerous cancers. However, the functions of circRNAs in intrahepatic cholangiocarcinoma (ICC) are still unclear. METHODS: circPCNXL2 (has_circ_0016956) were identified in paired ICC by circRNA microarray. Then, we assessed the biological functions of circPCNXL2 by CCK8, EdU, clone formation, transwell, wound healing assays, and xenograft models. RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between cirrcPCNXL2 and serine-threonine kinase receptor-associated protein (STRAP). RNA pull-down, RIP and luciferase reporter assays were used to investigate the sponge functions of circPCNXL2. In the end, we explore the effects of circPCNXL2 and trametinib (a MEK1/2 inhibitor) in vivo. RESULTS: circPCNXL2 was upregulated in ICC tissues and cell lines, which promoted the proliferation and metastasis of ICC in vitro and in vivo. In terms of the mechanisms, circPCNXL2 could directly bind to STRAP and induce the interaction between STRAP and MEK1/2, resulting in the tumor promotion in ICC by activation of ERK/MAPK pathways. Besides, circPCNXL2 could regulate the expression of SRSF1 by sponging miR-766-3p and subsequently facilitated the growth of ICC. Finally, circPCNXL2 could partially inhibit the anti-tumor activity of trametinib in vivo. CONCLUSION: circPCNXL2 played a crucial role in the progression of ICC by interacting with STRAP to activate the ERK signaling pathway, as well as by modulating the miR-766-3p/SRSF1 axis. These findings suggest that circPCNXL2 may be a promising biomarker and therapeutic target for ICC.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , MicroARNs , Humanos , ARN Circular/genética , Proliferación Celular/genética , Colangiocarcinoma/metabolismo , Transducción de Señal , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/metabolismo , MicroARNs/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Factores de Empalme Serina-Arginina/metabolismoRESUMEN
Since the large-scale outbreak of porcine epidemic diarrhoea (PED) in 2010, caused by the genotype 2 (G2) variant of the porcine epidemic diarrhoea virus (PEDV), pig farms in China, even those vaccinated with the G2b vaccine, have experienced infections from the G2a variant, leading to significant economic losses. This study successfully isolated the G2a strain DY2020 from positive small intestine contents (SICs) by blind passage on Vero cells for four generations. The SICs were taken from Daye, Hubei Province, China. The biological characteristics were identified by indirect immunofluorescence assay (IFA) and transmission electron microscopy (TEM). The growth kinetics of the strain on Vero cells were detected by TCID50, and the virus titre could reach 107.35 TCID50 ml-1 (SD: 5.07×106). The pathogenicity towards colostrum-deprived piglets was conducted by assessing faecal viral shedding, morphometric analysis of intestinal lesions, and immunohistochemical staining. The results showed that DY2020 was highly virulent to colostrum-deprived piglets, with severe watery diarrhoea and other clinical symptoms appeared at 6 h post-infection (h p.i.), and all died within 30 h. Pathological tissue examination results showed that the lesions mainly occurred in the intestines of piglets, causing pathological changes such as shortening of intestinal villi. In summary, the discovery of the G2a strain DY2020 in this study is of great significance for understanding Hubei PEDV and provides an important theoretical basis for the development of new efficient PEDV vaccines.
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Virus de la Diarrea Epidémica Porcina , Chlorocebus aethiops , Animales , Porcinos , Virulencia , Células Vero , China , Diarrea/veterinariaRESUMEN
Point-of-care testing (POCT) has attracted great interest because of its prominent advantages of rapidness, precision, portability, and real-time monitoring, thus becoming a powerful biomedical device in early clinical diagnosis and convenient medical treatments. However, its complicated manufacturing process and high expense severely impede mass production and broad applications. Herein, an innovative but inexpensive integrated sandwich-paper three-dimensional (3D) cell sensing device is fabricated to in situ wirelessly detect H2O2 released from living cells. The paper-based electrochemical sensing device was constructed by a sealed sandwiched bottom plastic film/fiber paper/top hole-centered plastic film that was printed with patterned electrodes. A new (Fe, Mn)3(PO4)2/N-doped carbon nanorod was developed and immobilized on the sensing carbon electrode while cell culture solution filled the exposed fiber paper, allowing living cells to grow on the fiber paper surrounding the electrode. Due to the significantly shortening diffusion distance to access the sensing sites by such a unique device and a rationally tuned ratio of Fe2+/Mn2+, the device exhibits a fast response time (0.2 s), a low detection limit (0.4 µM), and a wide detection range (2-3200 µM). This work offers great promise for a low-cost and highly sensitive POCT device for practical clinic diagnosis and broad POCT biomedical applications.
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MicroRNAs (miRNAs) play vital roles in biological activities, but their in vivo imaging is still challenging due to the low abundance and the lack of efficient fluorescent tools. RNA aptamers with high affinity and low background emerge for bioimaging yet suffering from low brightness. We introduce a rational design based on target-mediated entropy-driven toehold exchange (EDTE) to induce the release of RNA aptamer and subsequently light up corresponding fluorophore, which achieves selective imaging of miRNAs with good stability in both living cells and tumor-bearing mouse. Through tailoring recognition unit of the EDTE probes, highly sensitive imaging of different miRNAs including miRNA-125b and miRNA-21 is achieved, confirming its universal bioimaging applications. In comparison with the reported "one-to-one" model, the EDTE strategy shows a remarkable 4.6-time improvement in signal/noise ratio for intracellular imaging of the same miRNA. Particularly, it realizes sensitive imaging of miRNA in vivo, providing a promising tool in investigating functions and interactions of disease-associated miRNAs.
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Aptámeros de Nucleótidos , Entropía , Colorantes Fluorescentes , MicroARNs , MicroARNs/análisis , MicroARNs/metabolismo , Aptámeros de Nucleótidos/química , Animales , Colorantes Fluorescentes/química , Ratones , Humanos , Imagen Óptica , Ratones DesnudosRESUMEN
Metal phosphides with easy synthesis, controllable morphology, and high capacity are considered as potential anodes for sodium-ion batteries (SIBs). However, the inherent shortcomings of metal phosphating materials, such as conductivity, kinetics, volume strain, etc are not satisfactory, which hinders their large-scale application. Here, a CoP@carbon nanofibers-composite containing rich CoâNâC heterointerface and phosphorus vacancies grown on carbon cloth (CoP1-x@MEC) is synthesized as SIB anode to accomplish extraordinary capacity and ultra-long cycle life. The hybrid composite nanoreactor effectively impregnates defective CoP as active reaction center while offering CoâNâC layer to buffer the volume expansion during charge-discharge process. These vast active interfaces, favored electrolyte infiltration, and a well-structured ion-electron transport network synergistically improve Na+ storage and electrode kinetics. By virtue of these superiorities, CoP1-x@MEC binder-free anode delivers superb SIBs performance including a high areal capacity (2.47 mAh cm-2@0.2 mA cm-2), high rate capability (0.443 mAh cm-2@6 mA cm-2), and long cycling stability (300 cycles without decay), thus holding great promise for inexpensive binder-free anode-based SIBs for practical applications.
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Solar-driven carbon dioxide (CO2) methanation holds significant research value in the context of carbon emission reduction and energy crisis. However, this eight-electron catalytic reaction presents substantial challenges in catalytic activity and selectivity. In this regard, researchers have conducted extensive exploration and achieved significant developments. This review provides an overview of the recent advances and challenges in efficient selective photocatalytic CO2 methanation. It begins by discussing the fundamental principles and challenges in detail, analyzing strategies for improving the efficiency of photocatalytic CO2 conversion to CH4 comprehensively. Subsequently, it outlines the recent applications and advanced characterization methods for photocatalytic CO2 methanation. Finally, this review highlights the prospects and opportunities in this area, aiming to inspire CO2 conversion into high-value CH4 and shed light on the research of catalytic mechanisms.
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High-rate lithium/sodium ion batteries or capacitors are the most promising functional units to achieve fast energy storage that highly depends on charge host materials. Host materials with lamellar structures are a good choice for hybrid charge storage hosts (capacitor or redox type). Emerging layered transition metal carbo-chalcogenides (TMCC) with homogeneous sulfur termination are especially attractive for charge storage. Using density functional theory calculations, six of 30 potential TMCC are screened to be stable, metallic, anisotropic in electronic conduction and mechanical properties due to the lamellar structures. Raman, infrared active modes and frequencies of the six TMCC are well assigned. Interlayer coupling, especially binding energies predict that the bulk layered materials can be easily exfoliated into 2D monolayers. Moreover, Ti2S2C, Zr2S2C are identified as the most gifted Li+/Na+ anode materials with relatively high capacities, moderate volume expansion, relatively low Li+/Na+ migration barriers for batteries or ion-hybrid capacitors. This work provides a foundation for rational materials design, synthesis, and identification of the emerging 2D family of TMCC.
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N6 -methyladenosine (m6 A) is the most prevalent epigenetic modification on eukaryotic messenger RNAs. Recent studies have focused on elucidating the key role of m6 A modification patterns in tumor progression. However, the relationship between m6 A and transcriptional regulation remains elusive. Nanopore technology enables the quantification of m6 A levels at each genomic site. In this study, a pair of tumor tissues and adjacent normal tissues from clear cell renal cell carcinoma (ccRCC) surgical samples were collected for Nanopore direct RNA sequencing. We identified 9644 genes displaying anomalous m6 A modifications, with 5343 genes upregulated and 4301 genes downregulated. Among these, 5224 genes were regarded as dysregulated genes, encompassing abnormal regulation of both m6 A modification and RNA expression. Gene Set Enrichment Analysis revealed an enrichment of these genes in pathways related to renal system progress and fatty acid metabolic progress. Furthermore, the χ2 test demonstrated a significant association between the levels of m6 A in dysregulated genes and their transcriptional expression levels. Additionally, we identified four obesity-associated genes (FTO, LEPR, ADIPOR2, and NPY5R) among the dysregulated genes. Further analyses using public databases revealed that these four genes were all related to the prognosis and diagnosis of ccRCC. This study introduced the novel approach of employing conjoint analysis of m6 A modification and RNA expression based on Nanopore sequencing to explore potential disease-related genes. Our work demonstrates the feasibility of the application of Nanopore sequencing technology in RNA epigenetic regulation research and identifies new potential therapeutic targets for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Secuenciación de Nanoporos , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Transcriptoma , Epigenoma , Epigénesis Genética , ARN , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genéticaRESUMEN
MAIN CONCLUSION: Overexpression of MdLBD3 in Arabidopsis reduced sensitivity to salt and drought stresses and was instrumental in promoting early flowering. Salt and drought stresses have serious effects on plant growth. LATERAL ORGAN BOUNDARY DOMAIN (LBD) proteins are a plant-specific transcription factors (TFs) family and play important roles in plants in resisting to abiotic stress. However, about the function of LBDs in apple and other woody plants is little known. In this study, protein sequences of the LBD family TFs in apples were identified which contained conserved LOB domains. The qRT-PCR analysis showed that the MdLBD3 gene was widely expressed in various tissues and organs. The subcellular localization assay showed that the MdLBD3 protein was localized in the nucleus. Ectopic expression of MdLBD3 in Arabidopsis positively regulated its salt and drought resistance, and promoted early flowering. Collectively, these results showed that MdLBD3 improved the abiotic stress resistance, plant growth and development. Overall, this study provided a new gene for breeding that can increase the abiotic stress tolerance in apple.
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Arabidopsis , Malus , Factores de Transcripción , Sequías , Fitomejoramiento , Estrés Salino , Clonación MolecularRESUMEN
Low back pain is a common clinical symptom of intervertebral disc degeneration (IVDD), which seriously affects the quality of life of the patients. The abnormal apoptosis and senescence of nucleus pulposus cells (NPCs) play important roles in the pathogenesis of IVDD. PHLDA2 is an imprinted gene related to cell apoptosis and tumour progression. However, its role in NPC degeneration is not yet clear. Therefore, this study was set to explore the effects of PHLDA2 on NPC senescence and apoptosis and the underlying mechanisms. The expression of PHLDA2 was examined in human nucleus pulposus (NP) tissues and NPCs. Immunohistochemical staining, magnetic resonance imaging imaging and western blot were performed to evaluate the phenotypes of intervertebral discs. Senescence and apoptosis of NPCs were assessed by SA-ß-galactosidase, flow cytometry and western blot. Mitochondrial function was investigated by JC-1 staining and transmission electron microscopy. It was found that the expression level of PHLDA2 was abnormally elevated in degenerated human NP tissues and NPCs. Furthermore, knockdown of PHLDA2 can significantly inhibit senescence and apoptosis of NPCs, whereas overexpression of PHLDA2 can reverse senescence and apoptosis of NPCs in vitro. In vivo experiment further confirmed that PHLDA2 knockdown could alleviate IVDD in rats. Knockdown of PHLDA2 could also reverse senescence and apoptosis in IL-1ß-treated NPCs. JC-1 staining indicated PHLDA2's knockdown impaired disruption of the mitochondrial membrane potential and also ameliorated superstructural destruction of NPCs as showed by transmission electron microscopy. Finally, we found the PHLDA2 knockdown promoted Collagen-II expression and suppressed MMP3 expression in NPCs by repressing wnt/ß-catenin pathway. In conclusion, the results of the present study showed that PHLDA2 promotes IL-1ß-induced apoptosis and senescence of NP cells via mitochondrial route by activating the Wnt/ß-catenin pathway, and suggested that therapy targeting PHLDA2 may provide valuable insights into possible IVDD therapies.
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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad-spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti-SFTSV effect of type â and â ¢ interferons (IFNs). IFITM3 overexpression exhibits anti-SFTSV function by blocking Gn/Gc-mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3-Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3-Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs-mediated anti-SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.
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Factores de Restricción Antivirales , Infecciones por Bunyaviridae , Síndrome de Trombocitopenia Febril Grave , Humanos , Infecciones por Bunyaviridae/inmunología , Proteínas de la Membrana/inmunología , Phlebovirus , Proteínas de Unión al ARN/inmunología , Síndrome de Trombocitopenia Febril Grave/inmunología , Proteínas Virales/metabolismo , Internalización del Virus , Factores de Restricción Antivirales/inmunologíaRESUMEN
A conditionally pathogenic bacterium called Bibersteinia trehalosi inhabits the upper respiratory tract of ruminants and is becoming a significant cause of pneumonia, especially in goats. In this study, we identified a gram-negative bacteria strain isolated from dead goat's lungs, which was named M01. By integrating the outcomes of its morphological and biochemical characterization with the investigation of the 16S rRNA gene sequence analysis, the isolate was identified as B. trehalosi. Based on antibiotic susceptibility tests, the isolate was shown to be resistant to ß-lactams, tetracyclines, and amphenicols. Its genome was discovered to comprise 2115 encoded genes and a circular chromosome measuring 2,345,568 bp using whole genome sequencing. Annotation of the VFBD database revealed that isolate M01 had four virulence genes encoding three virulence factors. The CARD database revealed that its genome has two antibiotic-resistance genes. Based on pathogenicity testing, isolate M01 was highly pathogenic to mice, primarily causing pneumonia, with an LD50 of 1.31 × 107 CFU/ml. Moreover, histopathology showed loss of alveolar structure and infiltration of lung inflammatory cells. Hence, the current study could provide sufficient information for prevention and control strategies for future epidemics of B. trehalosi in goat species.