RESUMEN
Eukaryotic organisms adapt to environmental fluctuations by altering their epigenomic landscapes and transcriptional programs. Nucleosomal histones carry vital epigenetic information and regulate gene expression, yet the mechanisms underlying chromatin-bound histone exchange remain elusive. Here, we found that histone H2Bs are globally degraded in Caenorhabditis elegans during starvation. Our genetic screens identified mutations in ubiquitin and ubiquitin-related enzymes that block H2B degradation in starved animals, identifying lysine 31 as the crucial residue for chromatin-bound H2B ubiquitination and elimination. Retention of aberrant nucleosomal H2B increased the association of the FOXO transcription factor DAF-16 with chromatin, generating an ectopic gene expression profile detrimental to animal viability when insulin/IGF signaling was reduced in well-fed animals. Furthermore, we show that the ubiquitin-proteasome system regulates chromosomal histone turnover in human cells. During larval development, C. elegans epidermal cells undergo H2B turnover after fusing with the epithelial syncytium. Thus, histone degradation may be a widespread mechanism governing dynamic changes of the epigenome.
Asunto(s)
Caenorhabditis elegans , Histonas , Animales , Humanos , Histonas/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Insulina/metabolismo , Cromatina , Ubiquitinación , Ubiquitina/metabolismoRESUMEN
The selective photocatalytic conversion of CO2 and H2O to high value-added C2H4 remains a great challenge, mainly attributed to the difficulties in C-C coupling of reaction intermediates and desorption of C2H4* intermediates from the catalyst surface. These two key issues can be simultaneously overcome by alloying Ag with Cu which gives enhanced activity to both reactions. Herein, we developed a facile stepwise photodeposition strategy to load Cu-Ag alloy sub-nanoclusters (ASNCs) on TiO2 for CO2 photoreduction to produce C2H4. The optimized catalyst exhibits a record-high C2H4 formation rate (1110.6 ± 82.5 µmol g-1 h-1) with selectivity of 49.1 ± 1.9%, which is an order-of-magnitude enhancement relative to current work for C2H4 photosynthesis. The in situ FT-IR spectra combined with DFT calculations reveal the synergistic effect of Cu and Ag in Cu-Ag ASNCs, which enable an excellent C-C coupling capability like Ag and promoted C2H4* desorption property like Cu, thus advancing the selective and efficient production of C2H4. The present work provides a deeper understanding on cluster chemistry and C-C coupling mechanism for CO2 reduction on ASNCs and develops a feasible strategy for photoreduction CO2 to C2 fuels or industrial feedstocks.
RESUMEN
Voltage-sensitive dyes (VSDs) are used to image electrical activity in cells and tissues with submillisecond time resolution. Most of these fast sensors are constructed from push-pull chromophores whose fluorescence spectra are modulated by the electric field across the cell membrane. It was found that the substitution of naphthalene with chromene produces a 60 to 80 nm red-shift in absorption and emission spectra while maintaining fluorescence quantum efficiency and voltage sensitivity. One dye was applied to ex vivo murine heart with excitation at 730 nm, by far the longest wavelength reported in voltage imaging. This VSD resolves cardiac action potentials in single trials with 12% ΔF/F per action potential. The well-separated excitation spectra between these long-wavelength VSDs and channelrhodopsin (ChR2) enabled monitoring of action potential propagation in ChR2 hearts without any perturbation of electrical dynamics. Importantly, by employing spatially localized optogenetic manipulation, action potential dynamics can be assessed in an all-optical fashion with no artifact related to optical cross-talk between the reporter and actuator. These new environmentally sensitive chromene-based chromophores are also likely to have applications outside voltage imaging.
Asunto(s)
Colorantes Fluorescentes , Corazón , Ratones , Animales , Potenciales de Acción/fisiología , Corazón/fisiología , FluorescenciaRESUMEN
BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Quimioradioterapia , Quimioterapia de Inducción , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Persona de Mediana Edad , Masculino , Femenino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/tratamiento farmacológico , Adulto , China/epidemiología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/terapia , Quimioradioterapia/métodos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anciano , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Adulto Joven , Adolescente , Supervivencia sin ProgresiónRESUMEN
Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which is responsible for enormous economic losses to the global pig industry. Although vaccination has been used to prevent PRV infection, the effectiveness of vaccines has been greatly diminished with the emergence of PRV variants. Therefore, there is an urgent need to develop anti-PRV drugs. Polyethylenimine (PEI) is a cationic polymer and has a wide range of antibacterial and antiviral activities. This study found that a low dose of 1 µg/mL of the 25-kDa linear PEI had significantly specific anti-PRV activity, which became more intense with increasing concentrations. Mechanistic studies revealed that the viral adsorption stage was the major target of PEI without affecting viral entry, replication stages, and direct inactivation effects. Subsequently, we found that cationic polymers PEI and Polybrene interfered with the interaction between viral proteins and cell surface receptors through electrostatic interaction to exert the antiviral function. In conclusion, cationic polymers such as PEI can be a category of options for defense against PRV. Understanding the anti-PRV mechanism also deepens host-virus interactions and reveals new drug targets for anti-PRV.IMPORTANCEPolyethylenimine (PEI) is a cationic polymer that plays an essential role in the host immune response against microbial infections. However, the specific mechanisms of PEI in interfering with pseudorabies virus (PRV) infection remain unclear. Here, we found that 25-kDa linear PEI exerted mechanisms of antiviral activity and the target of its antiviral activity was mainly in the viral adsorption stage. Correspondingly, the study demonstrated that PEI interfered with the virus adsorption stage by electrostatic adsorption. In addition, we found that cationic polymers are a promising novel agent for controlling PRV, and its antiviral mechanism may provide a strategy for the development of antiviral drugs.
Asunto(s)
Antivirales , Herpesvirus Suido 1 , Polietileneimina , Electricidad Estática , Animales , Adsorción/efectos de los fármacos , Antivirales/química , Antivirales/farmacología , Herpesvirus Suido 1/efectos de los fármacos , Herpesvirus Suido 1/metabolismo , Polietileneimina/química , Polietileneimina/farmacología , Seudorrabia/tratamiento farmacológico , Seudorrabia/virología , Porcinos/virología , Enfermedades de los Porcinos/virologíaRESUMEN
Viruses employ a series of diverse translational strategies to expand their coding capacity, which produces viral proteins with common domains and entangles virus-host interactions. P3N-PIPO, which is a transcriptional slippage product from the P3 cistron, is a potyviral protein dedicated to intercellular movement. Here, we show that P3N-PIPO from watermelon mosaic virus (WMV) triggers cell death when transiently expressed in Cucumis melo accession PI 414723 carrying the Wmr resistance gene. Surprisingly, expression of the P3N domain, shared by both P3N-PIPO and P3, can alone induce cell death, whereas expression of P3 fails to activate cell death in PI 414723. Confocal microscopy analysis revealed that P3N-PIPO targets plasmodesmata (PD) and P3N associates with PD, while P3 localizes in endoplasmic reticulum in melon cells. We also found that mutations in residues L35, L38, P41, and I43 of the P3N domain individually disrupt the cell death induced by P3N-PIPO, but do not affect the PD localization of P3N-PIPO. Furthermore, WMV mutants with L35A or I43A can systemically infect PI 414723 plants. These key residues guide us to discover some WMV isolates potentially breaking the Wmr resistance. Through searching the NCBI database, we discovered some WMV isolates with variations in these key sites, and one naturally occurring I43V variation enables WMV to systemically infect PI 414723 plants. Taken together, these results demonstrate that P3N-PIPO, but not P3, is the avirulence determinant recognized by Wmr, although the shared N terminal P3N domain can alone trigger cell death.IMPORTANCEThis work reveals a novel viral avirulence (Avr) gene recognized by a resistance (R) gene. This novel viral Avr gene is special because it is a transcriptional slippage product from another virus gene, which means that their encoding proteins share the common N-terminal domain but have distinct C-terminal domains. Amazingly, we found that it is the common N-terminal domain that determines the Avr-R recognition, but only one of the viral proteins can be recognized by the R protein to induce cell death. Next, we found that these two viral proteins target different subcellular compartments. In addition, we discovered some virus isolates with variations in the common N-terminal domain and one naturally occurring variation that enables the virus to overcome the resistance. These results show how viral proteins with common domains interact with a host resistance protein and provide new evidence for the arms race between plants and viruses.
Asunto(s)
Enfermedades de las Plantas , Potyvirus , Proteínas Virales , Enfermedades de las Plantas/virología , Potyvirus/genética , Potyvirus/patogenicidad , Proteínas Virales/genética , Proteínas Virales/metabolismo , Cucumis melo/virología , Resistencia a la Enfermedad/genética , Muerte Celular , Plasmodesmos/virología , Plasmodesmos/metabolismo , Virulencia , Cucurbitaceae/virología , Interacciones Huésped-Patógeno , Retículo Endoplásmico/virología , Retículo Endoplásmico/metabolismo , Mutación , Citrullus/virologíaRESUMEN
Hepatocellular carcinoma (HCC) is one of the most fatal malignancies. Early diagnosis of HCC is crucial in reducing the risk for mortality. This study analyzed a panel of nine fusion transcripts in serum samples from 61 patients with HCC and 75 patients with non-HCC conditions, using TaqMan real-time quantitative RT-PCR. Seven of the nine fusions frequently detected in patients with HCC included: MAN2A1-FER (100%), SLC45A2-AMACR (62.3%), ZMPSTE24-ZMYM4 (62.3%), PTEN-NOLC1 (57.4%), CCNH-C5orf30 (55.7%), STAMBPL1-FAS (26.2%), and PCMTD1-SNTG1 (16.4%). Machine-learning models were constructed based on serum fusion-gene levels to predict HCC in the training cohort, using the leave-one-out cross-validation approach. One machine-learning model, called the four fusion genes logistic regression model (MAN2A1-FER≤40, CCNH-C5orf30≤38, SLC45A2-AMACR≤41, and PTEN-NOLC1≤40), produced accuracies of 91.5% and 83.3% in the training and testing cohorts, respectively. When serum α-fetal protein level was incorporated into the machine-learning model, a two fusion gene (MAN2A1-FER≤40, CCNH-C5orf30≤38) + α-fetal protein logistic regression model was found to generate an accuracy of 94.8% in the training cohort. The same model resulted in 95% accuracy in both the testing and combined cohorts. Cancer treatment was associated with reduced levels of most of the serum fusion transcripts. Serum fusion-gene machine-learning models may serve as important tools in screening for HCC and in monitoring the impact of HCC treatment.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , Aprendizaje Automático , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Adulto , Proteínas de Fusión Oncogénica/genéticaRESUMEN
14-3-3 proteins play vital roles in plant defense against various pathogen invasions. To date, how 14-3-3 affects virus infections in plants remains largely unclear. In this study, we found that Nicotiana benthamiana 14-3-3h interacts with TRANSLATIONALLY CONTROLLED TUMOR PROTEIN (TCTP), a susceptibility factor of potato virus Y (PVY). Silencing of Nb14-3-3h facilitates PVY accumulation, whereas overexpression of Nb14-3-3h inhibits PVY replication. The antiviral activities of 3 Nb14-3-3h dimerization defective mutants are significantly decreased, indicating that dimerization of Nb14-3-3h is indispensable for restricting PVY infection. Our results also showed that the mutant Nb14-3-3hE16A, which is capable of dimerizing but not interacting with NbTCTP, has reduced anti-PVY activity; the mutant NbTCTPI65A, which is unable to interact with Nb14-3-3h, facilitates PVY replication compared with the wild-type NbTCTP, indicating that dimeric Nb14-3-3h restricts PVY infection by interacting with NbTCTP and preventing its proviral function. As a counter-defense, PVY 6K1 interferes with the interaction between Nb14-3-3h and NbTCTP by competitively binding to Nb14-3-3h and rescues NbTCTP to promote PVY infection. Our results provide insights into the arms race between plants and potyviruses.
Asunto(s)
Potyvirus , Virosis , Humanos , Proteínas 14-3-3 , Dimerización , Proteínas Virales/genéticaRESUMEN
BACKGROUND: Painful physical symptoms (PPS) are highly prevalent in patients with major depressive disorder (MDD). Presence of PPS in depressed patients are potentially associated with poorer antidepressant treatment outcome. We aimed to evaluate the association of baseline pain levels and antidepressant treatment outcomes. METHODS: We searched PubMed, Embase and Cochrane Library databases from inception through February 2023 based on a pre-registered protocol (PROSPERO: CRD42022381349). We included original studies that reported pretreatment pain measures in antidepressant treatment responder/remitter and non-responder/non-remitter among patients with MDD. Data extraction and quality assessment were performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses by two reviewers independently. The primary outcome was the difference of the pretreatment pain levels between antidepressant treatment responder/remitter and non-responder/non-remitter. Random-effects meta-analysis was used to calculate effect sizes (Hedge's g) and subgroup and meta-regression analyses were used to explore sources of heterogeneity. RESULTS: A total of 20 studies were included. Six studies reported significantly higher baseline pain severity levels in MDD treatment non-responders (Hedge's g = 0.32; 95% CI, 0.13-0.51; P = 0.0008). Six studies reported the presence of PPS (measured using a pain severity scale) was significantly associated with poor treatment response (OR = 1.46; 95% CI, 1.04-2.04; P = 0.028). Five studies reported significant higher baseline pain interference levels in non-responders (Hedge's g = 0.46; 95% CI, 0.32-0.61; P < 0.0001). Four studies found significantly higher baseline pain severity levels in non-remitters (Hedge's g = 0.27; 95% CI, 0.14-0.40; P < 0.0001). Eight studies reported the presence of PPS significantly associated with treatment non-remission (OR = 1.70; 95% CI, 1.24-2.32; P = 0.0009). CONCLUSIONS: This study suggests that PPS are negatively associated with the antidepressant treatment outcome in patients with MDD. It is possible that better management in pain conditions when treating depression can benefit the therapeutic effects of antidepressant medication in depressed patients.
RESUMEN
Previous studies have shown that excessive alcohol consumption is associated with poor sleep. However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits (e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population. To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization (MR) design. Observational analyses and one-sample MR (linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank (UKB). Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia. Phenotype analyses were externally validated using data from the National Health and Nutrition Examination Survey (2017-2018). Data analysis was conducted from January 2022 to October 2022. The association between alcohol consumption and six self-reported sleep traits (short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia) were analysed. This study included 383,357 UKB participants (mean [SD] age, 57.0 [8.0] years; 46% male) who consumed a mean (SD) of 9.0 (10.0) standard drinks (one standard drink equivalent to 14 g of alcohol) per week. In the observational analyses, alcohol consumption was significantly associated with all sleep traits. Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping. In linear MR analyses, a 1-SD (14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold (95% CI, 1.07-1.22) higher risk of snoring (P < 0.001), a 1.28-fold (95% CI, 1.20-1.37) higher risk of evening chronotype (P < 0.001) and a 1.24-fold (95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning (P < 0.001). Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment. The results of the two-sample MR analyses were consistent with those of the one-sample MR analyses, but with a slightly attenuated overall estimate. Our findings suggest that even low levels of alcohol consumption may affect sleep health, particularly by increasing the risk of snoring and evening chronotypes. The negative effects of alcohol consumption on sleep should be made clear to the public in order to promote public health.
Asunto(s)
Consumo de Bebidas Alcohólicas , Bancos de Muestras Biológicas , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Trastornos del Inicio y del Mantenimiento del Sueño , Sueño , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/epidemiología , Masculino , Reino Unido/epidemiología , Femenino , Persona de Mediana Edad , Sueño/genética , Sueño/fisiología , Anciano , Trastornos del Inicio y del Mantenimiento del Sueño/genética , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Ronquido/genética , Ronquido/epidemiología , Adulto , Fenotipo , Trastornos del Sueño-Vigilia/genética , Trastornos del Sueño-Vigilia/epidemiología , Polimorfismo de Nucleótido Simple/genética , Biobanco del Reino UnidoRESUMEN
Non-small-cell lung cancer (NSCLC), a common malignant tumor, requires deeper pathogenesis investigation. Autophagy is an evolutionarily conserved lysosomal degradation process that is frequently blocked during cancer progression. It is an urgent need to determine the novel autophagy-associated regulators in NSCLC. Here, we found that pirin was upregulated in NSCLC, and its expression was positively correlated with poor prognosis. Overexpression of pirin inhibited autophagy and promoted NSCLC proliferation. We then performed data-independent acquisition-based quantitative proteomics to identify the differentially expressed proteins (DEPs) in pirin-overexpression (OE) or pirin-knockdown (KD) cells. Among the pirin-regulated DEPs, ornithine decarboxylase 1 (ODC1) was downregulated in pirin-KD cells while upregulated along with pirin overexpression. ODC1 depletion reversed the pirin-induced autophagy inhibition and pro-proliferation effect in A549 and H460 cells. Immunohistochemistry showed that ODC1 was highly expressed in NSCLC cancer tissues and positively related with pirin. Notably, NSCLC patients with pirinhigh/ODC1high had a higher risk in terms of overall survival. In summary, we identified pirin and ODC1 as a novel cluster of prognostic biomarkers for NSCLC and highlighted the potential oncogenic role of the pirin/ODC1/autophagy axis in this cancer type. Targeting this pathway represents a possible therapeutic approach to treat NSCLC.
Asunto(s)
Autofagia , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Progresión de la Enfermedad , Neoplasias Pulmonares , Ornitina Descarboxilasa , Femenino , Humanos , Masculino , Células A549 , Autofagia/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Ornitina Descarboxilasa/metabolismo , Ornitina Descarboxilasa/genética , Pronóstico , Regulación hacia ArribaRESUMEN
RB1 deficiency leads to retinoblastoma (Rb), the most prevalent intraocular malignancy. Tumor-associated macrophages (TAMs) are related to local inflammation disorder, particularly by increasing cytokines and immune escape. Microglia, the unique resident macrophages for retinal homeostasis, are the most important immune cells of Rb. However, whether RB1 deficiency affects microglial function remain unknown. In this study, microglia were successfully differentiated from Rb patient- derived human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs), and then we investigated the function of RB1 in microglia by live imaging phagocytosis assay, immunofluorescence, RNA-seq, qRT-PCR, ELISA and retina organoids/microglia co-culturing. RB1 was abundantly expressed in microglia and predominantly located in the nucleus. We then examined the phagocytosis ability and secretion function of iMGs in vitro. We found that RB1 deficiency did not affect the expression of microglia-specific markers or the phagocytic abilities of these cells by live-imaging. Upon LPS stimulation, RB1-deficient microglia displayed enhanced innate immune responses, as evidenced by activated MAPK signaling pathway and elevated expression of IL-6 and TNF-α at both mRNA and protein levels, compared to wildtype microglia. Furthermore, retinal structure disruption was observed when retinal organoids were co-cultured with RB1-deficient microglia, highlighting the potential contribution of microglia to Rb development and potential therapeutic strategies for retinoblastoma.
Asunto(s)
Células Madre Pluripotentes Inducidas , Neoplasias de la Retina , Retinoblastoma , Humanos , Retinoblastoma/genética , Retinoblastoma/metabolismo , Retinoblastoma/patología , Microglía/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Retina , Neoplasias de la Retina/genética , Neoplasias de la Retina/metabolismo , Neoplasias de la Retina/patologíaRESUMEN
BACKGROUND: The hair follicle development process is regulated by sophisticated genes and signaling networks, and the hair grows from the hair follicle. The Tianzhu white yak population exhibits differences in hair length, especially on the forehead and shoulder region. However, the genetic mechanism is still unclear. Isoform sequencing (Iso-seq) technology with advantages in long reads sequencing. Hence, we combined the Iso-seq and RNA-seq methods to investigate the transcript complexity and difference between long-haired yak (LHY) and normal-haired yak (NHY). RESULTS: The hair length measurement result showed a significant difference between LHY and NHY on the forehead and the shoulder (P-value < 0.001). The skin samples from the forehead and the shoulder of LHY and NHY were pooled for isoform sequencing (Iso-seq). We obtained numerous long transcripts, including novel isoforms, long non-coding RNA, alternative splicing events, and alternative polyadenylation events. Combined with RNA-seq data, we performed differential isoforms (DEIs) analysis between LHY and NHY. We found that some hair follicle and skin development-related DEIs, like BMP4, KRT2, IGF2R, and COL1A2 in the forehead skin; BMP1, KRT1, FGF5, COL2A1, and IGFBP5 in the shoulder skin. Enrichment analysis revealed that DEIs in both two comparable groups significantly participated in skin and hair follicle development-related pathways, like ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathways. The results indicated that the hair follicle development of Tianzhu white yak may influence the hair length difference. Besides, the protein-protein interaction (PPI) network of DEIs showed COL2A1 and COL3A1 exhibited a high degree of centrality, and these two genes were suggested as potential candidates for the hair length growth of Tianzhu white yak. CONCLUSIONS: The results provided a comprehensive analysis of the transcriptome complexity and identified differential transcripts that enhance our understanding of the molecular mechanisms underlying the variation in hair length growth in Tianzhu white yak.
Asunto(s)
Cabello , Isoformas de Proteínas , RNA-Seq , Piel , Transcriptoma , Animales , Bovinos/genética , Piel/metabolismo , Cabello/metabolismo , Cabello/crecimiento & desarrollo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Folículo Piloso/metabolismo , Folículo Piloso/crecimiento & desarrollo , Perfilación de la Expresión Génica , Empalme Alternativo , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: There is no consensus as to the origin of the domestic yak (Bos grunniens). Previous studies on yak mitochondria mainly focused on mitochondrial displacement loop (D-loop), a region with low phylogenetic resolution. Here, we analyzed the entire mitochondrial genomes of 509 yaks to obtain greater phylogenetic resolution and a comprehensive picture of geographical diversity. RESULTS: A total of 278 haplotypes were defined in 509 yaks from 21 yak breeds. Among them, 28 haplotypes were shared by different varieties, and 250 haplotypes were unique to specific varieties. The overall haplotype diversity and nucleotide diversity of yak were 0.979 ± 0.0039 and 0.00237 ± 0.00076, respectively. Phylogenetic tree and network analysis showed that yak had three highly differentiated genetic branches with high support rate. The differentiation time of clades I and II were about 0.4328 Ma, and the differentiation time of clades (I and II) and III were 0.5654 Ma. Yushu yak is shared by all haplogroups. Most (94.70%) of the genetic variation occurred within populations, and only 5.30% of the genetic variation occurred between populations. The classification showed that yaks and wild yaks were first clustered together, and yaks were clustered with American bison as a whole. Altitude had the highest impact on the distribution of yaks. CONCLUSIONS: Yaks have high genetic diversity and yak populations have experienced population expansion and lack obvious phylogeographic structure. During the glacial period, yaks had at least three or more glacial refugia.
Asunto(s)
Variación Genética , Genoma Mitocondrial , Haplotipos , Filogenia , Filogeografía , Animales , Bovinos/genética , Herencia Materna , Femenino , ADN Mitocondrial/genéticaRESUMEN
Pseudorabies have caused enormous economic losses in China's pig industry and have recurred on many large pig farms since late 2011. The disease is caused by highly pathogenic, antigenic variant pseudorabies virus (vPRV) strains. Our laboratory isolated a pseudorabies virus in 2015 and named it XJ5. The pathogenic ability of this mutant strain was much stronger than that of the original isolate. After we sequenced its whole genome (GenBank accession number: OP512542), we found that its overall structure was not greatly changed compared with that of the previous strain Ea (KX423960.1). The whole genome alignment showed that XJ5 had a strong genetic relationship with the strains isolated in China after 2012 reported in GenBank. Based on the isolation time of XJ5 and the mutation and recombination analysis of programs, we found that the whole genome homology of XJ5 and other strains with Chinese isolates was greater than 95%, while the homology with strains outside Asia was less than 94%, which indicated that there may be some recombination and mutation patterns. We found that virulent PRV isolates emerged successively in China in 2011 and formed two different evolutionary clades from foreign isolates. At the same time, this may be due to improper immunization and the presence of wild strains in the field, and recent reports have confirmed that Bartha vaccine strains recombine with wild strains to obtain new pathogenic strains. We performed genetic evolution analysis of XJ5 isolated and sequenced in our laboratory to trace its possible mutations and recombination. We found that XJ5 may be the result of natural mutation of a virus in a branch of mutant strains widely existing in China.
Asunto(s)
Evolución Molecular , Genoma Viral , Herpesvirus Suido 1 , Mutación , Filogenia , Seudorrabia , Recombinación Genética , Herpesvirus Suido 1/genética , Herpesvirus Suido 1/aislamiento & purificación , China , Animales , Porcinos , Seudorrabia/virología , Enfermedades de los Porcinos/virología , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: DNA sequencing is a critical tool in modern biology. Over the last two decades, it has been revolutionized by the advent of massively parallel sequencing, leading to significant advances in the genome and transcriptome sequencing of various organisms. Nevertheless, challenges with accuracy, lack of competitive options and prohibitive costs associated with high throughput parallel short-read sequencing persist. RESULTS: Here, we conduct a comparative analysis using matched DNA and RNA short-reads assays between Element Biosciences' AVITI and Illumina's NextSeq 550 chemistries. Similar comparisons were evaluated for synthetic long-read sequencing for RNA and targeted single-cell transcripts between the AVITI and Illumina's NovaSeq 6000. For both DNA and RNA short-read applications, the study found that the AVITI produced significantly higher per sequence quality scores. For PCR-free DNA libraries, we observed an average 89.7% lower experimentally determined error rate when using the AVITI chemistry, compared to the NextSeq 550. For short-read RNA quantification, AVITI platform had an average of 32.5% lower error rate than that for NextSeq 550. With regards to synthetic long-read mRNA and targeted synthetic long read single cell mRNA sequencing, both platforms' respective chemistries performed comparably in quantification of genes and isoforms. The AVITI displayed a marginally lower error rate for long reads, with fewer chemistry-specific errors and a higher mutation detection rate. CONCLUSION: These results point to the potential of the AVITI platform as a competitive candidate in high-throughput short read sequencing analyses when juxtaposed with the Illumina NextSeq 550.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ARN/métodos , Humanos , Análisis de la Célula Individual/métodos , Biblioteca de GenesRESUMEN
Prostate cancer remains one of the most fatal malignancies in men in the United States. Predicting the course of prostate cancer is challenging given that only a fraction of prostate cancer patients experience cancer recurrence after radical prostatectomy or radiation therapy. This study examined the expressions of 14 fusion genes in 607 prostate cancer samples from the University of Pittsburgh, Stanford University, and the University of Wisconsin-Madison. The profiling of 14 fusion genes was integrated with Gleason score of the primary prostate cancer and serum prostate-specific antigen level to develop machine-learning models to predict the recurrence of prostate cancer after radical prostatectomy. Machine-learning algorithms were developed by analysis of the data from the University of Pittsburgh cohort as a training set using the leave-one-out cross-validation method. These algorithms were then applied to the data set from the combined Stanford/Wisconsin cohort (testing set). The results showed that the addition of fusion gene profiling consistently improved the prediction accuracy rate of prostate cancer recurrence by Gleason score, serum prostate-specific antigen level, or a combination of both. These improvements occurred in both the training and testing cohorts and were corroborated by multiple models.
Asunto(s)
Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Antígeno Prostático Específico/genética , Recurrencia Local de Neoplasia/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Próstata/patología , Prostatectomía , PronósticoRESUMEN
Bound states in the continuum (BIC) offer great design freedom for realizing high-quality factor metasurfaces. By deliberately disrupting the inherent symmetries, BIC can degenerate into quasi-BIC exhibiting sharp spectra with strong light confinement. This transformation has been exploited to develop cutting-edge sensors and modulators. However, most proposed quasi-BICs in metasurfaces are composed of unit cells with Cs symmetry that may experience performance degradation due to polarization deviation, posing challenges in practical applications. Addressing this critical issue, our research introduces an innovative approach by incorporating metasurfaces with C4v unit cell symmetry to eliminate polarization response sensitivity. Vanadium Dioxide (VO2) is a phase-change material with a relatively low transition temperature and reversibility. Here, we theoretically investigate the polarization-insensitive quasi-BIC modulation in Si-VO2 hybrid metasurfaces. By introducing defects into metasurfaces with Cs, C4, and C4v symmetries, we enable the emergence of quasi-BICs characterized by strong Fano resonance in their transmission spectra. Via numerically calculating the multipole decomposition, distinct dominant multipoles for different quasi-BICs are identified. A comprehensive investigation into the polarization responses of these structures under varying directions of linearly polarized light reveals the superior polarization-independent characteristics of metasurfaces with C4 and C4v symmetries, a feature that ensures the maintenance of maximum resonance peaks irrespective of polarization direction. Utilizing the polarization-insensitive quasi-BIC, we thus designed two different Si-VO2 hybrid metasurfaces with C4v symmetry. Each configuration presents complementary benefits, leveraging the VO2 phase transition's loss change to facilitate efficient modulation. Our quantitative calculation indicates notable achievements in modulation depth, with a maximum relative modulation depth reaching up to 342%. For the first time, our research demonstrates efficient modulation using polarization-insensitive quasi-BICs in designed Si-VO2 hybrid metasurfaces, achieving identical polarization responses for quasi-BIC-based applications. Our work paves the way for designing polarization-independent quasi-BICs in metasurfaces and marks a notable advancement in the field of tunable integrated devices.
RESUMEN
In this Letter, we demonstrate a high-power ytterbium-doped fiber laser (YDFL) based on a directly in-band pumping scheme (DIPS) which employs 1018 nm laser diodes (LDs) as pump sources. The wavelength of the LDs is designed theoretically, considering the distribution of Yb3+ absorption cross section (σa) as well as quantum defect (QD). The flat distribution of σa around 1018 nm ensures excellent temperature insensitivity and flexibility for the YDFL. Besides, lower QD and more compact structure promise higher optical-to-optical (O-O) and electrical-to-optical (E-O) efficiencies. Based on the experimental setup, as the cooling temperature of the 1018 nm LDs ranges from 6 to 23°C, an output power of 2 kW level is achieved that varies by only 2.01% without adjusting the operating current of the LDs subjectively. The output power is then scaled up to 5 kW level. Furthermore, there is a great potential to achieve higher output power and E-O efficiency in YDFLs based on the DIPS.
RESUMEN
The ovary as one of the most dynamic organs produces steroids to orchestrate female secondary sexual characteristics, harbors ovarian reserve for oocytes, releases mature oocytes for fertilization, and maintains pregnancy. Yak (Bos grunniens) is the only bovid animal that can adapt to the harsh climatic conditions on the Qinghai-Tibetan Plateau (altitudes of over 3000 m above sea level). However, the cellular atlas is composed of oocytes and other somatic cells, and their individual molecular characteristics remain to be elucidated in the yak ovary. Here, single-cell RNA sequencing (scRNA-seq) was performed to delineate the molecular signature of various cell types in the yak ovarian cortex. A cellular atlas of yak ovarian cortex was constructed successfully on the basis of the differentially expressed genes (DEGs) from the distinct cell types and their functional enrichment analysis, comprising endothelial cells, nature kill cells, stromal cells, smooth muscle cells, oocytes, macrophages, epithelial cells, and granulosa cells. Meanwhile, the signature genes were determined based on their expression specificity in each cell type. A cell-to-cell communication network was built in light of the differentially overexpressed ligand and receptor genes from each cell type. Further, the oocytes were subdivided into four subtypes based on their individual DEGs and the functional enrichment of the DEGs. FST and TOP2A were identified as maker genes for oocytes by immunostaining in the yak ovarian cortex. The cellular atlas reveals the biological characteristics of the ovarian cortex at the cellular molecular level and provides insights into female reproductive biology via cellular communications in the yak.