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CD4+ T cells are central to various immune responses, but the molecular programs that drive and maintain CD4+ T cell immunity are not entirely clear. Here we identify a stem-like program that governs the CD4+ T cell response in transplantation models. Single-cell-transcriptomic analysis revealed that naive alloantigen-specific CD4+ T cells develop into TCF1hi effector precursor (TEP) cells and TCF1-CXCR6+ effectors in transplant recipients. The TCF1-CXCR6+CD4+ effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1hiCD4+ TEP cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1-CXCR6+ effectors from TCF1hiCD4+ TEP cells. Mechanistically, TCF1 sustains the CD4+ TEP cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4+ TEP cells. Deletion of IRF4 or LDHA in T cells induces transplant acceptance. These findings unravel a stem-like program that controls the self-renewal capacity and effector differentiation potential of CD4+ TEP cells and have implications for T cell-related immunotherapies.
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Regulación de la Expresión Génica , Linfocitos T Reguladores , Diferenciación CelularRESUMEN
Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well characterized, but little is known about the mechanisms by which ADs effect gene activation. Here, we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.
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Células Madre Embrionarias de Ratones/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Receptores de Estrógenos/metabolismo , Activación Transcripcional/fisiología , Animales , Células HEK293 , Humanos , Ratones , Células Madre Embrionarias de Ratones/citología , Factor 3 de Transcripción de Unión a Octámeros/genética , Dominios Proteicos , Receptores de Estrógenos/genéticaRESUMEN
There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.
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Elementos de Facilitación Genéticos , Regiones Promotoras Genéticas , Factor de Transcripción YY1/metabolismo , Animales , Factor de Unión a CCCTC/metabolismo , Células Madre Embrionarias/metabolismo , Humanos , RatonesRESUMEN
Translation is pervasive outside of canonical coding regions, occurring in long noncoding RNAs, canonical untranslated regions and introns1-4, especially in ageing4-6, neurodegeneration5,7 and cancer8-10. Notably, the majority of tumour-specific antigens are results of noncoding translation11-13. Although the resulting polypeptides are often nonfunctional, translation of noncoding regions is nonetheless necessary for the birth of new coding sequences14,15. The mechanisms underlying the surveillance of translation in diverse noncoding regions and how escaped polypeptides evolve new functions remain unclear10,16-19. Functional polypeptides derived from annotated noncoding sequences often localize to membranes20,21. Here we integrate massively parallel analyses of more than 10,000 human genomic sequences and millions of random sequences with genome-wide CRISPR screens, accompanied by in-depth genetic and biochemical characterizations. Our results show that the intrinsic nucleotide bias in the noncoding genome and in the genetic code frequently results in polypeptides with a hydrophobic C-terminal tail, which is captured by the ribosome-associated BAG6 membrane protein triage complex for either proteasomal degradation or membrane targeting. By contrast, canonical proteins have evolved to deplete C-terminal hydrophobic residues. Our results reveal a fail-safe mechanism for the surveillance of unwanted translation from diverse noncoding regions and suggest a possible biochemical route for the preferential membrane localization of newly evolved proteins.
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Código Genético , Biosíntesis de Proteínas , Proteínas , ARN Largo no Codificante , Ribosomas , Humanos , Chaperonas Moleculares/metabolismo , Péptidos/química , Péptidos/genética , Péptidos/metabolismo , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Ribosomas/metabolismo , ARN Largo no Codificante/genética , Biosíntesis de Proteínas/genética , Genoma Humano , Código Genético/genética , Interacciones Hidrofóbicas e Hidrofílicas , Intrones/genéticaRESUMEN
As a plant-specific transcription factor, lateral organ boundaries domain (LBD) protein was reported to regulate plant growth and stress response, but the functional research of subfamily II genes is limited. SlMYC2, a master regulator of Jasmonic acid response, has been found to exhibit high expression levels in fruit and has been implicated in the regulation of fruit ripening and resistance to Botrytis. However, its role in fruit expansion remains unknown. In this study, we present evidence that a subfamily II member of LBD, namely SlLBD40, collaborates with SlMYC2 in the regulation of fruit expansion. Overexpression of SlLBD40 significantly promoted fruit growth by promoting mesocarp cell expansion, while knockout of SlLBD40 showed the opposite result. Similarly, SlMYC2 knockout resulted in a significant decrease in cell expansion within the fruit. Genetic analysis indicated that SlLBD40-mediated cell expansion depends on the expression of SlMYC2. SlLBD40 bound to the promoter of SlEXPA5, an expansin gene, but did not activate its expression directly. While, the co-expression of SlMYC2 and SlLBD40 significantly stimulated the activation of SlEXPA5, leading to an increase in fruit size. SlLBD40 interacted with SlMYC2 and enhanced the stability and abundance of SlMYC2. Furthermore, SlMYC2 directly targeted and activated the expression of SlLBD40, which is essential for SlLBD40-mediated fruit expansion. In summary, our research elucidates the role of the interaction between SlLBD40 and SlMYC2 in promoting cell expansion in tomato fruits, thus providing novel insights into the molecular genetics underlying fruit growth.
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Frutas , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas , Solanum lycopersicum , Factores de Transcripción , Solanum lycopersicum/genética , Solanum lycopersicum/crecimiento & desarrollo , Solanum lycopersicum/metabolismo , Frutas/genética , Frutas/crecimiento & desarrollo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Plantas Modificadas Genéticamente , Regiones Promotoras Genéticas/genéticaRESUMEN
Isocitrate dehydrogenase gene (IDH) mutation is one of the most important molecular markers of glioma. Accurate detection of IDH status is a crucial step for integrated diagnosis of adult-type diffuse gliomas. Herein, a clustering-based hybrid of a convolutional neural network and a vision transformer deep learning model was developed to detect IDH mutation status from annotation-free hematoxylin and eosin-stained whole slide pathologic images of 2275 adult patients with diffuse gliomas. For comparison, a pure convolutional neural network, a pure vision transformer, and a classic multiple-instance learning model were also assessed. The hybrid model achieved an area under the receiver operating characteristic curve of 0.973 in the validation set and 0.953 in the external test set, outperforming the other models. The hybrid model's ability in IDH detection between difficult subgroups with different IDH status but shared histologic features, achieving areas under the receiver operating characteristic curve ranging from 0.850 to 0.985 in validation and test sets. These data suggest that the proposed hybrid model has a potential to be used as a computational pathology tool for preliminary rapid detection of IDH mutation from whole slide images in adult patients with diffuse gliomas.
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Neoplasias Encefálicas , Glioma , Adulto , Humanos , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Imagen por Resonancia Magnética/métodos , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/patología , Mutación/genética , Estudios RetrospectivosRESUMEN
Articular cartilage injury is one of the most common diseases in orthopedic clinics. Following an articular cartilage injury, an inability to resist vascular invasion can result in cartilage calcification by newly formed blood vessels. This process ultimately leads to the loss of joint function, significantly impacting the patient's quality of life. As a result, developing anti-angiogenic methods to repair damaged cartilage has become a popular research topic. Despite this, tissue engineering, as an anti-angiogenic strategy in cartilage injury repair, has not yet been adequately investigated. This exhaustive literature review mainly focused on the process and mechanism of vascular invasion in articular cartilage injury repair and summarized the major regulatory factors and signaling pathways affecting angiogenesis in the process of cartilage injury. We aimed to discuss several potential methods for engineering cartilage repair with anti-angiogenic strategies. Three anti-angiogenic tissue engineering methods were identified, including administering angiogenesis inhibitors, applying scaffolds to manage angiogenesis, and utilizing in vitro bioreactors to enhance the therapeutic properties of cultured chondrocytes. The advantages and disadvantages of each strategy were also analyzed. By exploring these anti-angiogenic tissue engineering methods, we hope to provide guidance for researchers in related fields for future research and development in cartilage repair.
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Cartílago Articular , Calidad de Vida , Humanos , Inmunoterapia , Inhibidores de la Angiogénesis , Calcificación FisiológicaRESUMEN
OBJECTIVE: ASPP1 (apoptosis stimulating of p53 protein 1) is critical in regulating cell apoptosis as a cofactor of p53 to promote its transcriptional activity in the nucleus. However, whether cytoplasmic ASPP1 affects p53 nuclear trafficking and its role in cardiac diseases remains unknown. This study aims to explore the mechanism by which ASPP1 modulates p53 nuclear trafficking and the subsequent contribution to cardiac ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: The immunofluorescent staining showed that under normal condition ASPP1 and p53 colocalized in the cytoplasm of neonatal mouse ventricular cardiomyocytes, while they were both upregulated and translocated to the nuclei upon hypoxia/reoxygenation treatment. The nuclear translocation of ASPP1 and p53 was interdependent, as knockdown of either ASPP1 or p53 attenuated nuclear translocation of the other one. Inhibition of importin-ß1 resulted in the cytoplasmic sequestration of both p53 and ASPP1 in neonatal mouse ventricular cardiomyocytes with hypoxia/reoxygenation stimulation. Overexpression of ASPP1 potentiated, whereas knockdown of ASPP1 inhibited the expression of Bax (Bcl2-associated X), PUMA (p53 upregulated modulator of apoptosis), and Noxa, direct apoptosis-associated targets of p53. ASPP1 was also increased in the I/R myocardium. Cardiomyocyte-specific transgenic overexpression of ASPP1 aggravated I/R injury as indicated by increased infarct size and impaired cardiac function. Conversely, knockout of ASPP1 mitigated cardiac I/R injury. The same qualitative data were observed in neonatal mouse ventricular cardiomyocytes exposed to hypoxia/reoxygenation injury. Furthermore, inhibition of p53 significantly blunted the proapoptotic activity and detrimental effects of ASPP1 both in vitro and in vivo. CONCLUSIONS: Binding of ASPP1 to p53 triggers their nuclear cotranslocation via importin-ß1 that eventually exacerbates cardiac I/R injury. The findings imply that interfering the expression of ASPP1 or the interaction between ASPP1 and p53 to block their nuclear trafficking represents an important therapeutic strategy for cardiac I/R injury.
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Proteínas Adaptadoras Transductoras de Señales , Daño por Reperfusión , Proteína p53 Supresora de Tumor , Animales , Ratones , Apoptosis/fisiología , Hipoxia/metabolismo , Isquemia/metabolismo , Carioferinas , Miocitos Cardíacos/metabolismo , Daño por Reperfusión/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
The synthesis of pre-mRNA by RNA polymerase II (Pol II) involves the formation of a transcription initiation complex, and a transition to an elongation complex1-4. The large subunit of Pol II contains an intrinsically disordered C-terminal domain that is phosphorylated by cyclin-dependent kinases during the transition from initiation to elongation, thus influencing the interaction of the C-terminal domain with different components of the initiation or the RNA-splicing apparatus5,6. Recent observations suggest that this model provides only a partial picture of the effects of phosphorylation of the C-terminal domain7-12. Both the transcription-initiation machinery and the splicing machinery can form phase-separated condensates that contain large numbers of component molecules: hundreds of molecules of Pol II and mediator are concentrated in condensates at super-enhancers7,8, and large numbers of splicing factors are concentrated in nuclear speckles, some of which occur at highly active transcription sites9-12. Here we investigate whether the phosphorylation of the Pol II C-terminal domain regulates the incorporation of Pol II into phase-separated condensates that are associated with transcription initiation and splicing. We find that the hypophosphorylated C-terminal domain of Pol II is incorporated into mediator condensates and that phosphorylation by regulatory cyclin-dependent kinases reduces this incorporation. We also find that the hyperphosphorylated C-terminal domain is preferentially incorporated into condensates that are formed by splicing factors. These results suggest that phosphorylation of the Pol II C-terminal domain drives an exchange from condensates that are involved in transcription initiation to those that are involved in RNA processing, and implicates phosphorylation as a mechanism that regulates condensate preference.
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Complejo Mediador/química , Complejo Mediador/metabolismo , ARN Polimerasa II/química , ARN Polimerasa II/metabolismo , Empalme del ARN , Transcripción Genética , Animales , Línea Celular , Elementos de Facilitación Genéticos/genética , Regulación de la Expresión Génica/genética , Humanos , Complejo Mediador/genética , Ratones , Fosforilación , Dominios Proteicos , ARN Polimerasa II/genética , Factores de Empalme de ARN/química , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismoRESUMEN
The importance of mechanosensory transduction pathways in cellular signalling has prominently come to focus in the last decade with the discovery of the Piezo ion channel family. Mechanosignaling involving Piezo1 ion channels in the function of the heart and cardiovascular system has only recently been identified to have implications for cardiovascular physiology and pathophysiology, in particular for heart failure (i.e., hypertrophy or dilative cardiomyopathy). These results have emphasized the need for higher throughput methods to study single-cell cardiovascular mechanobiology with the aim of identifying new targets for therapeutic interventions and stimulating the development of new pharmacological agents. Here, we present a novel method to assess mechanosignaling in adherent cardiac cells (murine HL-1 cell line) using a combination of isotropic cell stretch application and simultaneous Ca2+ fluorescence readout with quantitative analysis. The procedure implements our IsoStretcher technology in conjunction with a single-cell- and population-based analysis of Ca2+ signalling by means of automated image registration, cell segmentation and analysis, followed by automated classification of single-cell responses. The method is particularly valuable for assessing the heterogeneity of populations with distinct cellular responses to mechanical stimulation and provides more user-independent unbiased drug response classifications.
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Canales Iónicos , Mecanotransducción Celular , Ratones , Animales , Canales Iónicos/metabolismo , Transducción de Señal , Corazón , Línea CelularRESUMEN
Drought is the most severe form of stress experienced by plants worldwide. Cucumber is a vegetable crop that requires a large amount of water throughout the growth period. In our previous study, we identified that overexpression of CsHSFA1d could improve cold tolerance and the content of endogenous jasmonic acid in cucumber seedlings. To explore the functional diversities of CsHSFA1d, we treat the transgenic plants under drought conditions. In this study, we found that the heat shock transcription factor HSFA1d (CsHSFA1d) could improve drought stress tolerance in cucumber. CsHSFA1d overexpression increased the expression levels of galactinol synthase (CsGolS3) and raffinose synthase (CsRS) genes, encoding the key enzymes for raffinose family oligosaccharide (RFO) biosynthesis. Furthermore, the lines overexpressing CsHSFA1d showed higher enzymatic activity of GolS and raffinose synthase to increase the content of RFO. Moreover, the CsHSFA1d-overexpression lines showed lower reactive oxygen species (ROS) accumulation and higher ROS-scavenging enzyme activity after drought treatment. The expressions of antioxidant genes CsPOD2, CsAPX1 and CsSOD1 were also upregulated in CsHSFA1d-overexpression lines. The expression levels of stress-responsive genes such as CsRD29A, CsLEA3 and CsP5CS1 were increased in CsHSFA1d-overexpression lines after drought treatment. We conclude that CsHSFA1d directly targets and regulates the expression of CsGolS3 and CsRS to promote the enzymatic activity and accumulation of RFO to increase the tolerance to drought stress. CsHSFA1d also improves ROS-scavenging enzyme activity and gene expression indirectly to reduce drought-induced ROS overaccumulation. This study therefore offers a new gene target to improve drought stress tolerance in cucumber and revealed the underlying mechanism by which CsHSFA1d functions in the drought stress by increasing the content of RFOs and scavenging the excessive accumulation of ROS.
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Cucumis sativus , Galactosiltransferasas , Regulación de la Expresión Génica de las Plantas , Oligosacáridos , Proteínas de Plantas , Plantas Modificadas Genéticamente , Rafinosa , Especies Reactivas de Oxígeno , Cucumis sativus/genética , Cucumis sativus/fisiología , Cucumis sativus/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rafinosa/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Oligosacáridos/metabolismo , Galactosiltransferasas/metabolismo , Galactosiltransferasas/genética , Sequías , Factores de Transcripción del Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico/genética , Estrés Fisiológico/genéticaRESUMEN
Alternating current electroluminescence (ACEL) devices are attractive candidates in cost-effective lighting, sensing, and flexible displays due to their uniform luminescence, stable performance, and outstanding deformability. However, ACEL devices have suffered from limited options for the light-emitting layer, which presents a significant constraint in the progress of utilizing ACEL. Herein, a new class of ACEL phosphors based on lanthanide metal-organic frameworks (Ln-MOFs) is devised. A synthesis of lanthanide-benzenetricarboxylate (Ln-BTC) thin film on a brass grid substrate seeded with ZnO nanowires (NWs) as anchors is developed. The as-synthesized Ln-BTC thin film is employed as the emissive layer and shows visible electroluminescence driven by alternating current (2.9 V µm-1 , 1 kHz) for the first time. Mechanistic investigations reveal that the Ln-based ACEL stems from impact excitation by accelerated electrons from ZnO NWs. Fine-tuning of the ACEL color is also demonstrated by controlling the Ln-MOF compositions and introducing an extra ZnS emitting layer. The advances in these optical materials expand the application of ACEL devices in anti-counterfeiting.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of deaths around the world. To help contribute to the understanding of crucial knowledge and to further generate new hypotheses relevant to SARS-CoV-2 and human protein interactions, we make use of the information abundant Biomine probabilistic database and extend the experimentally identified SARS-CoV-2-human protein-protein interaction (PPI) network in silico. We generate an extended network by integrating information from the Biomine database, the PPI network and other experimentally validated results. To generate novel hypotheses, we focus on the high-connectivity sub-communities that overlap most with the integrated experimentally validated results in the extended network. Therefore, we propose a new data analysis pipeline that can efficiently compute core decomposition on the extended network and identify dense subgraphs. We then evaluate the identified dense subgraph and the generated hypotheses in three contexts: literature validation for uncovered virus targeting genes and proteins, gene function enrichment analysis on subgraphs and literature support on drug repurposing for identified tissues and diseases related to COVID-19. The major types of the generated hypotheses are proteins with their encoding genes and we rank them by sorting their connections to the integrated experimentally validated nodes. In addition, we compile a comprehensive list of novel genes, and proteins potentially related to COVID-19, as well as novel diseases which might be comorbidities. Together with the generated hypotheses, our results provide novel knowledge relevant to COVID-19 for further validation.
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COVID-19 , Simulación por Computador , Modelos Biológicos , Mapas de Interacción de Proteínas , COVID-19/genética , COVID-19/metabolismo , Humanos , SARS-CoV-2/química , SARS-CoV-2/genética , SARS-CoV-2/metabolismoRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a common chronic skin disorder in children. We aimed to investigate trends and regional disparities of burden in paediatric AD at global, regional and national levels, and to explore potential associated factors. METHODS: Based on data from Global Burden of Disease study 2019, we assessed trends in burden of AD aged <19 years from 1990 to 2019, including prevalent and incident cases, age-standardised prevalence and age-standardised incidence. For potential associated factors, correlations of above trends and indexes of socio-economic status (sociodemographic index, SDI) and health service coverage (universal health coverage index, UHCI) were evaluated. We conducted decomposition analysis to understand the net contribution of population-level factors and their contribution proportions on changes of prevalent and incident cases, including age structure, population change and epidemiological change. RESULTS: Global prevalent and incident cases of paediatric AD increased by about 5.7 and 0.7 million between 1990 and 2019, respectively. Global age-standardised prevalence and incidence decreased by -0.17% (-0.19% to -0.16%) and -0.12% (-0.13% to -0.11%) per year from 1990 to 2019, respectively. Regionally, the highest increase of prevalent and incident cases was in low SDI region (by 96.77% and 84.85%); the highest decrease of age-standardised prevalence and incidence was in high SDI regions (by -0.20% and -0.27% per year). The correlation analyses identified significant negative correlations between trends and SDI and UHCI. Population change was a major driver of case rise; epidemiological change and age structure showed negative impact of case rise. Regional disparities in contribution of three population-level factors were seen, including net contribution direction (positive or negative) and contribution proportion levels. CONCLUSION: Global paediatric AD case numbers increased, primarily due to population growth. Prevalence and incidence decreased slightly. Geographic inequalities were seen. Developing region-specific strategies targeting potential factors is essential to reduce paediatric AD burden.
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There is often a trade-off effect between different agronomic traits due to gene pleiotropy, leading to a negative correlation between yield and resistance. Consequently, using gene-editing techniques to develop superior traits becomes challenging. Genetic resources that defy this constraint are scarce but hold great potential as targets for improvement through the utilisation of CRISPR. Transcription factors are critical in modulating numerous gene expressions across diverse biological processes. Here, we found that the trihelix transcription factor SlGT30 plays a role in drought resistance and tomato fruit development. We edited the SlGT30 gene with CRISPR/Cas9 technology and found that the knockout lines showed decreased stomata density in the leaves and large fruits. Subsequent examination revealed that cell ploidy was impacted in the leaves and fruits of SlGT30 knockout lines. SlGT30 knockout affected cell size through the endoreduplication pathway, manifested in decreased stomata density and reduced water loss. Consequently, this resulted in an enhancement of drought resistance. For the fruit, both cell size and cell number increased in the fruit pericarp of knockout lines, improving the fruit size and weight accordingly. Therefore, SlGT30 represents a promising candidate gene for gene editing in breeding practice.
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Vascular endothelial growth factor (VEGF) signaling is crucial for choroidal neovascularization (CNV), a major pathological feature of neovascular age-related macular degeneration (nAMD). Gene transcription of VEGF is mainly regulated by hypoxia-inducible factor 1-alpha (HIF-1α). The chromobox (CBX) family polycomb protein (Pc) subgroup includes CBX2, CBX4, CBX6, CBX7, and CBX8. CBX4 enhances hypoxia-induced VEGF expression and angiogenesis in hepatocellular carcinoma (HCC) cells by increasing HIF-1α's transcriptional activity. The objective of the study was to examine the functions of members of the CBX family Pc subgroup in choroidal vascular endothelial cells (CVECs) during CNV. CBX4 and CBX7 expression was up-regulated in hypoxic human choroidal vascular endothelial cells (HCVECs). In HCVECs, CBX7 facilitated HIF-1α transcription and expression, while CBX4 did not. In HCVECs, CBX7 stimulated HIF-1α's nuclear translocation and transcriptional activity, which in turn stimulated VEGF transcription and expression. The CBX7/HIF-1α/VEGF pathway promoted the migration, proliferation, and tube formation of HCVECs. The CBX7/HIF-1α/VEGF pathway was up-regulated in CVECs and in the mouse model with laser-induced CNV. Mouse CNV was lessened by the blockade of CBX7 through the down-regulation of HIF-1α/VEGF. In conclusion, CBX7 enhanced pro-angiogenic behaviors of hypoxic CVECs by up-regulating the HIF-1α/VEGF pathway, which contributing to the formation of mouse laser-induced CNV.
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Background: Systemic lupus erythematosus (SLE) is chronic autoimmune disease with multiple organ damage and is associated with poor prognosis and high mortality. Identification of universal biomarkers to predict SLE activity is challenging due to the heterogeneity of the disease. This study aimed to identify the indicators that are sensitive and specific to predict activity of SLE.Methods: We retrospectively analyzed 108 patients with SLE. Patients were categorized into SLE with activity and without activity groups on the basis of SLE disease activity index. We analyzed the potential of routine and novel indicators in predicting the SLE activity using receiver operating characteristic curves and multivariate logistic regression. The Spearman method was used to understand the correlation between albumin to fibrinogen ratio (AFR), prognostic nutritional index (PNI), AFR-PNI model and disease activity.Results: SLE with activity group had higher ESR, CRP, D-dimer, fibrinogen, CRP to albumin ratio, positive rate of anti-dsDNA and ANUA, and lower C3, total bilirubin, total protein, albumin, albumin/globulin, creatinine, high density liptein cholesterol, hemoglobin, hematocrit, lymphocyte count, positive rate of anti-SSA, AFR, PNI than SLE without activity. A further established model based on combination of AFR and PNI (AFR-PNI model) showed prominent value in distinguishing SLE with activity patients from SLE without activity patients. In addition, the sensitivity and specificity of AFR-PNI model + anti-dsDNA combination model were superior to AFR-PNI model. AFR and PNI were risk factors for SLE activity. Moreover, AFR+PNI model correlated with disease activity and AFR-PNI model was associated with fever, pleurisy, pericarditis, renal involvement.Conclusion: These findings suggest that predictive model based on combination of AFR and PNI may be useful markers to identify active SLE in clinical practice.
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Lupus Eritematoso Sistémico , Evaluación Nutricional , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/complicaciones , Fibrinógeno , Pronóstico , Estudios Retrospectivos , Biomarcadores , AlbúminasRESUMEN
The adiabatic connection (AC) approximation, along with its linearized variant AC0, was introduced as a method of obtaining dynamic correlation energy. When using a complete active space self-consistent field (CASSCF) wave function as a reference, the AC0 approximation is considered one of the most efficient multi-reference perturbation theories. It only involves the use of 1st- and 2nd-order reduced density matrices. However, some numerical results have indicated that the excitation energies predicted by AC0 are not as reliable as those from the second-order N-electron valence state perturbation theory (NEVPT2). In this study, we develop a spinless formulation of AC0 based on the Dyall Hamiltonian and provide a detailed comparison between AC0 and NEVPT2 approaches. We demonstrate the components within the correlation energy expressions that are common to both methods and those unique to either AC0 or NEVPT2. We investigate the role of the terms exclusive to NEVPT2 and explore the possibility of enhancing AC0's performance in this regard.
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In this study, we systematically investigated the regioselective glycosylation of 2,4-OH mannoside and galactoside acceptors since regioselective protection of their 3- and 6-OHs is readily achieved. By altering the protecting groups at 1-, 3-, and 6-positions of such acceptors, we finally screened p-methoxyphenyl 3-OBn, 6-OTBDPS, α-mannoside, and ß-galactoside acceptors whose 2-OHs exhibited excellent selectivity for glycosylation with various glycosyl donors, leading to 1,2-linked products in 70-82% yields. By utilizing such acceptors, a series of 2,4-linked trisaccharide products (53-65% yields over two steps) have been highly efficiently synthesized without the need for complex protection/deprotection operations at the 2- and 4-positions of these acceptors.
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Galectins are lectins that bind to ß-galactose and are widely expressed in immune system tissues, playing pivotal roles in innate immunity through their conserved carbohydrate-recognition domains (CRDs). In this present investigation, a tandem-repeat galectin was discovered in the largemouth bass, Micropterus salmoides (designated as MsGal-9). The open reading frame of MsGal-9 encodes two CRDs, each containing two consensus motifs that are essential for ligand binding. MsGal-9 is expressed in various tissues of the largemouth bass, with particularly high expression levels in the liver and spleen. The full-length form of MsGal-9, as well as the N-terminal (MsGal-9-N) and C-terminal (MsGal-9-C) CRDs, were individually recombined. Their ability for nonself recognition was studied. The three recombinant proteins were able to bind to glucan (GLU), peptidoglycan (PGN), and lipopolysaccharide (LPS), with MsGal-9 displaying the highest binding activity. Furthermore, rMsGal-9-N exhibited higher binding activity towards GLU in comparison to rMsGal-9-C. Further investigations revealed that the full-length rMsGal-9 could significantly bind to Gram-positive bacteria, Gram-negative bacteria, and fungi, while rMsGal-9-C specifically bound to Escherichia coli. However, rMsGal-9-N did not exhibit significant binding activity towards any microbes. These findings indicate that MsGal-9 requires both CRDs to cooperate in order to fulfill its nonself recognition function. All three recombinant proteins demonstrated agglutination activity towards various microbes, with MsGal-9 and MsGal-9-N displaying a similar broad binding spectrum, while MsGal-9-C agglutinated three types of bacteria. Moreover, both MsGal-9 and MsGal-9-N were capable of coagulating largemouth bass red blood cells, whereas MsGal-9-C lacked this ability. However, MsGal-9-C played a significant role in enhancing the encapsulation of leukocytes in comparison to MsGal-9-N. All three proteins acted as potential damage-associated molecular patterns (DAMPs), inducing apoptosis in leukocytes.