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METHODS: The study employed a retrospective survey of 458 older individuals with T2D residing in a Chinese community, conducted between June 2020 and May 2021, to develop a predictive model for frailty. Among the participants, 83 individuals (18.1%) were diagnosed with frailty using modified frailty phenotypic criteria. The predictors of frailty in this community-dwelling older population with T2D were determined using least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression. These predictors were utilized to construct a nomogram. The discrimination, calibration, and medical usefulness of the prediction model were assessed through the C-index, calibration plot, and decision curve analysis (DCA), respectively. Additionally, internal validation of the prediction model was conducted using bootstrapping validation. RESULTS: The developed nomogram for frailty prediction predominantly incorporated age, smoking status, regular exercise, depression, albumin (ALB) levels, sleep condition, HbA1c, and polypharmacy as significant predictors. Our prediction model demonstrated excellent discrimination and calibration, as evidenced by a C-index of 0.768 (95% CI, 0.714-0.822) and strong calibration. Internal validation yielded a C-index of 0.732, further confirming the reliability of the model. DCA indicated the utility of the nomogram in identifying frailty among the studied population. CONCLUSION: The development of a predictive model enables a valuable estimation of frailty among community-dwelling older individuals with type 2 diabetes. This evidence-based tool provides crucial guidance to community healthcare professionals in implementing timely preventive measures to mitigate the occurrence of frailty in high-risk patients. By identifying established predictors of frailty, interventions and resources can be appropriately targeted, promoting better overall health outcomes and improved quality of life in this vulnerable population.
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Robust genome editing technologies are becoming part of the crop breeding toolbox. Currently, genome editing is usually conducted either at a single locus, or multiple loci, in a variety at one time. Massively parallel genomics platforms, multifaceted genome editing capabilities, and flexible transformation systems enable targeted variation at nearly any locus, across the spectrum of genotypes within a species. We demonstrate here the simultaneous transformation and editing of many genotypes, by targeting mixed seed embryo explants with genome editing machinery, followed by re-identification through genotyping after plant regeneration. Transformation and Editing of Mixed Lines (TREDMIL) produced transformed individuals representing 101 of 104 (97%) mixed elite genotypes in soybean; and 22 of 40 (55%) and 9 of 36 (25%) mixed maize female and male elite inbred genotypes, respectively. Characterization of edited genotypes for the regenerated individuals identified over 800 distinct edits at the Determinate1 (Dt1) locus in samples from 101 soybean genotypes and 95 distinct Brown midrib3 (Bm3) edits in samples from 17 maize genotypes. These results illustrate how TREDMIL can help accelerate the development and deployment of customized crop varieties for future precision breeding. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00173-5.
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Epidural adhesion or epidural fibrosis is the major reason for postoperative pain, which remains a clinically challenging problem. Current physical barriers fail to provide a satisfactory therapeutic outcome mainly due to their lack of adhesion, inability to prevent fluid leakage, and exhibiting limited antioxidant properties. Herein, we fabricated a cysteine-modified bioadhesive (SECAgel) with improved sealing and antioxidant properties for epidural adhesion prevention, inspired by the organism's antioxidant systems. The resulting SECAgel showed good injectability and in situ adhesion ability, effectively covering every corner of the irregular wound. Besides, it possessed efficient sealing properties (395.2 mmHg), effectively stopping blood leakage in the rabbit carotid artery transection model. The antioxidant experiments demonstrated that the SECAgel effectively scavenged various radicals and saved the cells from oxidative stress. Two animal models were used to show that the SECAgel effectively inhibited adhesion in both situations with and without cerebrospinal fluid leakage. The RNA sequencing analysis showed that SECAgel treatment effectively inhibited the expression of key genes related to adhesion development, inflammatory response, and oxidative stress. The SECAgel, together with good biocompatibility, can be a good candidate for preventing epidural adhesion in the clinic.
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Antioxidantes , Animales , Conejos , Antioxidantes/farmacología , Antioxidantes/química , Adherencias Tisulares/prevención & control , Espacio Epidural/patología , Espacio Epidural/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Cisteína/química , Cisteína/farmacología , Humanos , Ratones , Adhesivos/química , Adhesivos/farmacología , MasculinoRESUMEN
High-resolution microscopy hyperspectral (HS) images can provide highly detailed spatial and spectral information, enabling the identification and analysis of biological tissues at a microscale level. Recently, significant efforts have been devoted to enhancing the resolution of HS images by leveraging high spatial resolution multispectral (MS) images. However, the inherent hardware constraints lead to a significant distribution gap between HS and MS images, posing challenges for image super-resolution within biomedical domains. This discrepancy may arise from various factors, including variations in camera imaging principles (e.g., snapshot and push-broom imaging), shooting positions, and the presence of noise interference. To address these challenges, we introduced a unique unsupervised super-resolution framework named R2D2-GAN. This framework utilizes a generative adversarial network (GAN) to efficiently merge the two data modalities and improve the resolution of microscopy HS images. Traditionally, supervised approaches have relied on intuitive and sensitive loss functions, such as mean squared error (MSE). Our method, trained in a real-world unsupervised setting, benefits from exploiting consistent information across the two modalities. It employs a game-theoretic strategy and dynamic adversarial loss, rather than relying solely on fixed training strategies for reconstruction loss. Furthermore, we have augmented our proposed model with a central consistency regularization (CCR) module, aiming to further enhance the robustness of the R2D2-GAN. Our experimental results show that the proposed method is accurate and robust for super-resolution images. We specifically tested our proposed method on both a real and a synthetic dataset, obtaining promising results in comparison to other state-of-the-art methods. Our code and datasets are accessible through Multimedia Content.
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The integrated fracturing and oil recovery strategy is a new paradigm for achieving sustainable and cost-effective development of unconventional reservoirs. However, a single type of working fluid cannot simultaneously meet the different needs of fracturing and oil displacement processes. Here, we develop a pH-responsive fracturing-displacement integrated working fluid based on the self-assembled micelles of N,N-dimethyl oleoamine propylamine (DOAPA) and succinic acid (SA). By adjusting the pH of the working fluid, the DOAPA and SA molecules can be switched repeatedly between highly viscoelastic wormlike micelles and aqueous low-viscosity spherical micelles. The zero-shear viscosity of the working fluid enriched the wormlike micelles can reach more than 93,100 mPa·s, showing excellent viscoelasticity and sand-carrying properties. The working fluid is easy to gel-break when it encounters oil, generating a low-viscosity liquid without residue. In addition, the system has strong interfacial activity, which can greatly reduce the oil-water interfacial tension to form emulsions and can achieve reversible demulsification and re-emulsification by adjusting pH. Through the designed and fabricated microfluidic chip, it can be visualized that under the synergistic effect of viscoelasticity and interfacial activity DOAPA/SA can effectively expand the swept volume of tight fractured formations, promote pore wetting reversal and crude oil emulsification, and improve the displacement efficiency. The DOAPA/SA meets the design requirements of the fracturing-displacement integrated working fluids and provides a novel method and idea for constructing the integrated working fluids suitable for fracturing and displacement in unconventional reservoirs.
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The clustered regularly interspaced short palindromic repeats (CRISPR) systems have been demonstrated to be the foremost compelling genetic tools for manipulating prokaryotic and eukaryotic genomes. Despite the robustness and versatility of Cas9 and Cas12a/b nucleases in mammalian cells and plants, their large protein sizes may hinder downstream applications. Therefore, investigating compact CRISPR nucleases will unlock numerous genome editing and delivery challenges that constrain genetic engineering and crop development. In this study, we assessed the archaeal miniature Un1Cas12f1 type-V CRISPR nuclease for genome editing in rice and tomato protoplasts. By adopting the reengineered guide RNA modifications ge4.1 and comparing polymerase II (Pol II) and polymerase III (Pol III) promoters, we demonstrated uncultured archaeon Cas12f1 (Un1Cas12f1) genome editing efficacy in rice and tomato protoplasts. We characterized the protospacer adjacent motif (PAM) requirements and mutation profiles of Un1Cas12f1 in both plant species. Interestingly, we found that Pol III promoters, not Pol II promoters, led to higher genome editing efficiency when they were used to drive guide RNA expression. Unlike in mammalian cells, the engineered Un1Cas12f1-RRA variant did not perform better than the wild-type Un1Cas12f1 nuclease, suggesting continued protein engineering and other innovative approaches are needed to further improve Un1Cas12f1 genome editing in plants.
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Edición Génica , Oryza , Solanum lycopersicum , Oryza/genética , Solanum lycopersicum/genética , Sistemas CRISPR-Cas , Protoplastos/metabolismo , Genoma de PlantaRESUMEN
BACKGROUND: The number of patients with type 1 diabetes rises rapidly around the world in recent years. Maternal diabetes has a detrimental effect on reproductive outcomes due to decreased oocyte quality. However, the strategies to improve the oocyte quality and artificial reproductive technology (ART) efficiency of infertile females suffering from diabetes have not been fully studied. In this study, we aimed to examine the effects of nicotinamide mononucleotide (NMN) on oocyte maturation of mouse with type 1 diabetes mouse and explore the underlying mechanisms of NMN's effect. METHODS: Streptozotocin (STZ) was used to establish the mouse models with type 1 diabetes. The successful establishment of the models was confirmed by the results of body weight test, fasting blood glucose test and haematoxylin and eosin (H&E) staining. The in vitro maturation (IVM) rate of oocytes from diabetic mice was examined. Immunofluorescence staining (IF) was performed to examine the reactive oxygen species (ROS) level, spindle/chromosome structure, mitochondrial function, actin dynamics, DNA damage and histone modification of oocytes, which are potential factors affecting the oocyte quality. The quantitative reverse transcription PCR (RT-qPCR) was used to detect the mRNA levels of Sod1, Opa1, Mfn2, Drp1, Sirt1 and Sirt3 in oocytes. RESULTS: The NMN supplementation increased the oocyte maturation rate of the mice with diabetes. Furthermore, NMN supplementation improved the oocyte quality by rescuing the actin dynamics, reversing meiotic defects, improving the mitochondrial function, reducing ROS level, suppressing DNA damage and restoring changes in histone modifications of oocytes collected from the mice with diabetes. CONCLUSION: NMN could improve the maturation rate and quality of oocytes in STZ-induced diabetic mice, which provides a significant clue for the treatment of infertility of the patients with diabetes.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Dinaminas , Mononucleótido de Nicotinamida , Oocitos , Especies Reactivas de Oxígeno , Animales , Ratones , Femenino , Oocitos/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Mononucleótido de Nicotinamida/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Sirtuina 1/metabolismo , Sirtuina 3/metabolismo , Técnicas de Maduración In Vitro de los Oocitos/métodos , Superóxido Dismutasa-1 , Daño del ADN/efectos de los fármacos , Estreptozocina , Oogénesis/efectos de los fármacosRESUMEN
Legume-based rotation is commonly recognized for its mitigation efficiency of greenhouse gas (GHG) emissions. However, variations in GHG emission-associated metabolic functions during the legume-vegetable rotation process remain largely uncharacterized. Accordingly, a soybean-radish rotation field experiment was designed to clarify the responses of microbial communities and their GHG emission-associated functional metabolism through metagenomics. The results showed that the contents of soil organic carbon and total phosphorus significantly decreased during the soybean-radish process (P < 0.05), while soil total potassium content and bacterial richness and diversity significantly increased (P < 0.05). Moreover, the predominant bacterial phyla varied, with a decrease in the relative abundance of Proteobacteria and an increase in the relative abundance of Acidobacteria, Gemmatimonadetes, and Chloroflexi. Metagenomics clarified that bacterial carbohydrate metabolism substantially increased during the rotation process, whereas formaldehyde assimilation, methanogenesis, nitrification, and dissimilatory nitrate reduction decreased (P < 0.05). Specifically, the expression of phosphate acetyltransferase (functional methanogenesis gene, pta) and nitrate reductase gamma subunit (functional dissimilatory nitrate reduction gene, narI) was inhibited, indicating of low methane production and nitrogen metabolism. Additionally, the partial least squares path model revealed that the Shannon diversity index was negatively correlated with methane and nitrogen metabolism (P < 0.01), further demonstrating that the response of the soil bacterial microbiome responses are closely linked with GHG-associated metabolism during the soybean-radish rotation process. Collectively, our findings shed light on the responses of soil microbial communities to functional metabolism associated with GHG emissions and provide important insights to mitigate GHG emissions during the rotational cropping of legumes and vegetables.
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Fabaceae , Gases de Efecto Invernadero , Verduras/metabolismo , Fabaceae/genética , Fabaceae/metabolismo , Nitratos , Carbono , Suelo , Metano/análisis , Nitrógeno/metabolismo , Dióxido de Carbono/análisis , AgriculturaRESUMEN
Hyperspectral images (HSIs) are composed of hundreds of contiguous waveband images, offering a wealth of spatial and spectral information. However, the practical use of HSIs is often hindered by the presence of complicated noise caused by various factors such as non-uniform sensor response and dark current. Traditional methods for denoising HSIs rely on constrained optimization approaches, where selecting appropriate prior knowledge is critical for achieving satisfactory results. Nevertheless, these traditional algorithms are limited by hand-crafted priors, leaving room for improvement in their denoising performance. Recently, the supervised deep learning technique has emerged as a promising approach for HSI denoising. However, their requirement for paired training data and poor generalization ability on untrained noise distributions pose challenges in practical applications. In this paper, we design a novel algorithm by the synergism of optimization-based methods and deep learning techniques. Specifically, we introduce a plug-and-play Deep Low-rank Decomposition (DLD) model into the optimization framework. Furthermore, we propose an effective mechanism to incorporate traditional prior knowledge into the DLD model. Finally, we provide a detailed analysis of the optimization process and convergence of the proposed method. Empirical evaluations on various tasks, including hyperspectral image denoising and spectral compressive imaging, demonstrate the superiority of our approach over state-of-the-art methods.
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Different degrees of roasting result in differences in the quality and flavor of large-leaf yellow tea. The current sensory evaluation and chemical detection methods cannot meet the requirement of online differentiation of LYT roasting degree, so an accurate and comprehensive assessment method needs to be developed urgently. First, the two aroma sensing technologies were compared. Two variable screening methods and three recognition algorithms were employed to build discriminant models. The results showed that the discrimination rate of the colorimetric sensor array (CSA) in the prediction set reached 91.89 %, outperforming that of the E-nose. Subsequently, three fusion strategies were applied to improve the discrimination accuracy. The discrimination rate of the middle fusion strategy resulted in an optimal resolution of 94.59 %. The results obtained from the homologous fusion were able to evaluate the roasting degree comprehensively and accurately, which provides a new method and idea for tea aroma quality.
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Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, ß-d-glucuronidases, and N-acetyl-glucosaminidases. The mode of inhibition of glucuronidases, in contrast to sialidases, has long been enigmatic as siastatin B appears too bulky and incorrectly substituted to be accommodated within a ß-d-glucuronidase active site pocket. Herein, we show through crystallographic analysis of protein-inhibitor complexes that siastatin B generates both a hemiaminal and a 3-geminal diol iminosugar (3-GDI) that are, rather than the parent compound, directly responsible for enzyme inhibition. The hemiaminal product is the first observation of a natural product that belongs to the noeuromycin class of inhibitors. Additionally, the 3-GDI represents a new and potent class of the iminosugar glycosidase inhibitor. To substantiate our findings, we synthesized both the gluco- and galacto-configured 3-GDIs and characterized their binding both structurally and kinetically to exo-ß-d-glucuronidases and the anticancer target human heparanase. This revealed submicromolar inhibition of exo-ß-d-glucuronidases and an unprecedented binding mode by this new class of inhibitor. Our results reveal the mechanism by which siastatin B acts as a broad-spectrum glycosidase inhibitor, identify a new class of glycosidase inhibitor, and suggest new functionalities that can be incorporated into future generations of glycosidase inhibitors.
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Inhibidores Enzimáticos , Glucuronidasa , Piperidinas , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Glucuronidasa/metabolismo , Glicósido Hidrolasas/metabolismoRESUMEN
To develop a comprehensive evaluation method for Keemun black tea, we used micro-near-infrared spectroscopy, computer vision, and colorimetric sensor array to collect data. We used support vector machine, least-squares support vector machine (LS-SVM), extreme learning machine, and partial least squares discriminant analysis algorithms to qualitatively discriminate between different grades of tea. Our results indicated that the LS-SVM model with mid-level data fusion attained an accuracy of 98.57% in the testing set. To quantitatively determine flavour substances in black tea, we used support vector regression. The correlation coefficient for the predicted sets of gallic acid, caffeine, epigallocatechin, catechin, epigallocatechin gallate, epicatechin, gallocatechin gallate and total catechins were 0.84089, 0.94249, 0.94050, 0.83820, 0.81111, 0.82670, 0.93230, and 0.93608, respectively. Furthermore, all compounds exhibited residual predictive deviation values exceeding 2. Hence, combining spectral, shape, colour, and aroma data with mid-level data can provide a rapid and comprehensive assessment of Keemun black tea quality.
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Oocyte senescence alters the shape and function, thereby weakening the fertilization potential. Nicotinamide mononucleotide (NMN) reverses age-related dysfunctions in various organs. Studies had shown long-term administration of NMN reduced the physiological decline associated in aged mice and reversed the aging of the ovaries. However, the protective effect of NMN on aged porcine oocytes is still unclear. In this study, we investigated the effects of NMN on aging porcine oocytes and subsequent embryonic development. We established a model of senescence of porcine oocytes after ovulation by extending the culture time in vitro. NMN supplementation significantly reduced reactive oxygen species (ROS) levels in senescence oocytes and increased the mRNA levels of antioxidant genes SOD1 and Cat. The mitochondrial membrane potential of aged oocytes treated with NMN was increased compared with that of untreated oocytes. In addition, the mRNA level of apoptosis-related gene Bax was significantly decreased in senescence oocytes treated with NMN, while the mRNA level of anti-apoptosis-related gene BCL-2 was significantly increased. Furthermore, NMN supplementation enhanced the subsequent development ability of senescent oocytes during in vitro aging. Compared with untreated senescent oocytes, the blastocyst formation rate and pluripotent genes of senescent oocytes treated with NMN were significantly increased. Taken together, these results suggest that NMN is beneficial for delaying the aging process in porcine oocytes.
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Técnicas de Maduración In Vitro de los Oocitos , Mononucleótido de Nicotinamida , Femenino , Porcinos , Animales , Ratones , Mononucleótido de Nicotinamida/farmacología , Técnicas de Maduración In Vitro de los Oocitos/métodos , Oocitos , Desarrollo Embrionario , Especies Reactivas de Oxígeno/farmacología , ARN Mensajero/farmacologíaRESUMEN
OBJECTIVES: To inform the impacts of health programmes which aimed at preventing women and children from being trapped in or returning to poverty because of illness in Yunnan, the main battlefield against poverty in China. DESIGN: The longitudinal comparative evaluation design. DATA COLLECTION AND ANALYSIS: National and Yunnan policy documents related to maternal and child health programmes for poverty alleviation during 2015-2020 were analysed. The changes in disparities in maternal and child health system inputs, service coverage, and health outcomes between poor and non-poor areas, as well as out-of-pocket payments between poor and non-poor populations were assessed before and after 2017. RESULTS: In total 12 policies and 15 programmes related to poverty alleviation for poor women and children in Yunnan were summarised. As a result of health system strengthening in Yunnan, the densities of licensed doctors, nurses, obstetricians, midwives, township health workers and female village doctors had been increased substantially in poor areas, with the annual rates of 14.3%, 22.5%, 21.8%, 23.9%, 14.1% and 7.1% separately. Although disparities existed in some of service coverage between poor and non-poor areas, the health programmes had narrowed the gaps in utilisation of facility birth, caesarean section, prenatal screening and newborn screening across Yunnan (p<0.01). The out-of-pocket payments for inpatient care for serious illnesses among women and children with poverty registration had been considerably decreased to 10.0%. Paralleling the universal coverage, maternal deaths per 100 000 livebirths and child deaths per 1000 livebirths had further declined in both poor and non-poor areas, and the impacts of health programmes on closing the gaps in child survivals across Yunnan were significant (p<0.01). CONCLUSIONS: Remarkable progress in equitable maternal and child survival has been achieved in Yunnan. The practices in Yunnan have shown the Chinese model in ending poverty by strengthening health system and implementing universal coverage with firm commitment, determined leadership, detailed blueprint and social participation.
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Servicios de Salud del Niño , Salud Infantil , Niño , Recién Nacido , Humanos , Femenino , Embarazo , Cesárea , China , PobrezaRESUMEN
Contamination, hazard level and source of 10 widely concerned potentially toxic metal(loid)s (PTMs) Co, As, Pb, Cr, Cu, Zn, Ni, Mn, Ba, and V in fine dust with particle size below 63 µm (FD63) were investigated to assess the environmental quality of college campuses and influencing factors. PTMs sources were qualitatively analyzed using statistical methods and quantitatively apportioned using positive matrix factorization. Probabilistic contamination degrees of PTMs were evaluated using enrichment factor and Nemerow integrated enrichment factor. Eco-health risk levels of content-oriented and source-oriented for PTMs were evaluated using Monte Carlo simulation. Mean levels of Zn (643.8 mg kg-1), Pb (146.0 mg kg-1), Cr (145.9 mg kg-1), Cu (95.5 mg kg-1), and Ba (804.2 mg kg-1) in FD63 were significantly larger than soil background values. The possible sources of the concerned PTMs in FD63 were traffic non-exhaust emissions, natural source, mixed source (auto repair waste, paints and pigments) and traffic exhaust emissions, which accounted for 45.7%, 25.4%, 14.5% and 14.4% of total PTMs contents, respectively. Comprehensive contamination levels of PTMs were very high, mainly caused by Zn pollution and non-exhaust emissions. Combined ecological risk levels of PTMs were low and moderate, chiefly caused by Pb and traffic exhaust emissions. The non-cancer risks of the PTMs in FD63 to college students fell within safety level, while the carcinogenic PTMs in FD63 had a certain cancer risks to college students. The results of source-specific health risk assessment indicated that Cr and As were the priority PTMs, and the mixed source was the priority pollution source of PTMs in FD63 from college campuses, which should be paid attention to by the local government.
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Metales Pesados , Contaminantes del Suelo , Humanos , Metales Pesados/análisis , Monitoreo del Ambiente/métodos , Polvo/análisis , Plomo , Método de Montecarlo , Contaminantes del Suelo/análisis , Medición de Riesgo , China , CiudadesRESUMEN
Preclinical trials play critical roles in assessing the safety and efficiency of novel therapeutic strategies for human diseases including live cancer. However, most therapeutic strategies that were proved to be effective in preclinical cancer models failed in human clinical trials due to the lack of appropriate disease animal models. Therefore, it is of importance and urgent to develop a precise animal model for preclinical cancer research. Liver cancer is one of the most frequently diagnosed cancers with low 5-year survival rate. Recently, porcine attracted increasing attentions as animal model in biomedical research. Porcine liver cancer model may provide a promising platform for biomedical research due to their similarities to human being in body size, anatomical characteristics, physiology and pathophysiology. In this review, we comprehensively summarized and discussed the advantages and disadvantages, rationale, current status and progress of pig models for liver cancer research.
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Investigación Biomédica , Neoplasias Hepáticas , Porcinos , Animales , Humanos , Modelos Animales de EnfermedadRESUMEN
After fertilization, sperm and oocyte fused and gave rise to a zygote which is the beginning of a new life. Then the embryonic development is monitored and regulated precisely from the transition of oocyte to the embryo at the early stage of embryogenesis, and this process is termed maternal-to-zygotic transition (MZT). MZT involves two major events that are maternal components degradation and zygotic genome activation. The epigenetic reprogramming plays crucial roles in regulating the process of MZT and supervising the normal development of early development of embryos. In recent years, benefited from the rapid development of low-input epigenome profiling technologies, new epigenetic modifications are found to be reprogrammed dramatically and may play different roles during MZT whose dysregulation will cause an abnormal development of embryos even abortion at various stages. In this review, we summarized and discussed the important novel findings on epigenetic reprogramming and the underlying molecular mechanisms regulating MZT in mammalian embryos. Our work provided comprehensive and detailed references for the in deep understanding of epigenetic regulatory network in this key biological process and also shed light on the critical roles for epigenetic reprogramming on embryonic failure during artificial reproductive technology and nature fertilization.
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Currently, anti-PD-1/PD-L1 immunotherapy using immune checkpoint inhibitors is widely used in the treatment of multiple cancer types including lung cancer, which is a leading cause of cancer death in the world. However, only a limited proportion of lung cancer patients will benefit from anti-PD-1/PD-L1 therapy. Therefore, it is of importance to predict the response to immunotherapy for the precision treatment of patients. Although the expression of PD-L1 and tumor mutation burden (TMB) are commonly used to predict the clinical response of anti-PD-1/PD-L1 therapy, other factors such as tumor-specific genes, dMMR/MSI, and gut microbiome are also promising predictors for immunotherapy in lung cancer. Furthermore, invasive peripheral blood biomarkers including blood DNA-related biomarkers (e.g., ctDNA and bTMB), blood cell-related biomarkers (e.g., immune cells and TCR), and other blood-related biomarkers (e.g., soluble PD-L1 and cytokines) were utilized to predict the immunotherapeutic response. In this review, the current achievements of anti-PD-1/PD-L1 therapy and the potential biomarkers for the prediction of anti-PD-1/PD-L1 immunotherapy in lung cancer treatment were summarized and discussed.
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Antígeno B7-H1 , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/metabolismo , Mutación , Neoplasias Pulmonares/tratamiento farmacológico , Biomarcadores de Tumor/genética , InmunoterapiaRESUMEN
Round spermatid injection (ROSI), one of the assistant reproductive technologies, was used to treat partial infertility patients suffering from non-obstructive azoospermia. However, the development efficiency and birth rate of ROSI embryos are extremely low, and it is urgent to investigate the underlying mechanisms of low efficiency to improve the clinical application of ROSI technology. Here, we analyzed and compared the genome stability of the mouse blastocyst and the post-implantation development between ROSI and ICSI embryos. We first sequenced the genome of blastocysts from mouse ROSI embryos that can correctly form male and female pronuclei (2 PN) and found that the genomes of 7 blastocysts were normal. Furthermore, the implantation rate of ROSI 2 PN embryos on embryonic day 7.5 is similar to that of ICSI embryos, and at this time, 37.50% (9/24) of deciduas have no normal gestational sac. The proportion of embryos that survived to embryonic day 11.5 in the ROSI 2 PN group, ROSI non-2 PN group, parthenogenesis group, and ICSI 2 PN group was 51.61%, 7.14%, 0.00%, and 55.00%, respectively. And two smaller fetuses were found in the ROSI 2 PN group, which is not found in the other three groups. In addition, the physiological indexes, including fetus and placenta weight, sex ratio, growth rate, and the natural breeding ability for the offspring obtained from mouse ROSI, were evaluated; ROSI mice exhibited no obvious defect or abnormality and implied that the progeny were safe. Our results provided new evidence to promote the clinical application of ROSI technology.
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Oocitos , Espermátides , Masculino , Femenino , Embarazo , Animales , Ratones , Oocitos/fisiología , Inyecciones de Esperma Intracitoplasmáticas/veterinaria , Desarrollo Embrionario , Partenogénesis , Blastocisto/fisiologíaRESUMEN
Genetic information is generally transferred from RNA to protein according to the classic "Central Dogma". Here, we made a striking discovery that post-translational modification of a protein specifically regulates the editing of its own mRNA. We show that S-nitrosylation of cathepsin B (CTSB) exclusively alters the adenosine-to-inosine (A-to-I) editing of its own mRNA. Mechanistically, CTSB S-nitrosylation promotes the dephosphorylation and nuclear translocation of ADD1, leading to the recruitment of MATR3 and ADAR1 to CTSB mRNA. ADAR1-mediated A-to-I RNA editing enables the binding of HuR to CTSB mRNA, resulting in increased CTSB mRNA stability and subsequently higher steady-state levels of CTSB protein. Together, we uncovered a unique feedforward mechanism of protein expression regulation mediated by the ADD1/MATR3/ADAR1 regulatory axis. Our study demonstrates a novel reverse flow of information from the post-translational modification of a protein back to the post-transcriptional regulation of its own mRNA precursor. We coined this process as "Protein-directed EDiting of its Own mRNA by ADAR1 (PEDORA)" and suggest that this constitutes an additional layer of protein expression control. "PEDORA" could represent a currently hidden mechanism in eukaryotic gene expression regulation.