RESUMEN
Wheat crops are frequently devastated by pandemic stripe rust caused by Puccinia striiformis f. sp. tritici (Pst). Here, we identify and characterize a wheat receptor-like cytoplasmic kinase gene, TaPsIPK1, that confers susceptibility to this pathogen. PsSpg1, a secreted fungal effector vital for Pst virulence, can bind TaPsIPK1, enhance its kinase activity, and promote its nuclear localization, where it phosphorylates the transcription factor TaCBF1d for gene regulation. The phosphorylation of TaCBF1d switches its transcriptional activity on the downstream genes. CRISPR-Cas9 inactivation of TaPsIPK1 in wheat confers broad-spectrum resistance against Pst without impacting important agronomic traits in two years of field tests. The disruption of TaPsIPK1 leads to immune priming without constitutive activation of defense responses. Taken together, TaPsIPK1 is a susceptibility gene known to be targeted by rust effectors, and it has great potential for developing durable resistance against rust by genetic modifications.
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Basidiomycota , Triticum , Basidiomycota/genética , Basidiomycota/metabolismo , Enfermedades de las Plantas , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Triticum/genética , Triticum/metabolismo , Triticum/microbiología , Virulencia/genéticaRESUMEN
Reactive oxygen species (ROS) are vital for plant immunity and regulation of their production is crucial for plant health. While the mechanisms that elicit ROS production have been relatively well studied, those that repress ROS generation are less well understood. Here, via screening Brachypodium distachyon RNA interference mutants, we identified BdWRKY19 as a negative regulator of ROS generation whose knockdown confers elevated resistance to the rust fungus Puccinia brachypodii. The three wheat paralogous genes TaWRKY19 are induced during infection by virulent P. striiformis f. sp. tritici (Pst) and have partially redundant roles in resistance. The stable overexpression of TaWRKY19 in wheat increased susceptibility to an avirulent Pst race, while mutations in all three TaWRKY19 copies conferred strong resistance to Pst by enhancing host plant ROS accumulation. We show that TaWRKY19 is a transcriptional repressor that binds to a W-box element in the promoter of TaNOX10, which encodes an NADPH oxidase and is required for ROS generation and host resistance to Pst. Collectively, our findings reveal that TaWRKY19 compromises wheat resistance to the fungal pathogen and suggest TaWRKY19 as a potential target to improve wheat resistance to the commercially important wheat stripe rust fungus.
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Basidiomycota , Triticum , Basidiomycota/metabolismo , Interacciones Huésped-Patógeno/genética , Enfermedades de las Plantas/microbiología , Especies Reactivas de Oxígeno/metabolismo , Triticum/metabolismoRESUMEN
BACKGROUND AND AIMS: It has been demonstrated that nitrogen (N) addition alters flower morphology, floral rewards and pollinator performance. However, little is known about the effects of N addition on plant reproduction, including fruit set and seed set during selfing and outcrossing, floral and vegetative traits, and pollinator performance. We hypothesized that N addition would influence fruit set, seed set in selfed and outcrossed flowers, the relationship between vegetative and flower traits, and pollinator performance. METHODS: A 2-year pot experiment was conducted in which Capsicum annuum was exposed to three levels of relatively short-term N supply, i.e. 0 g m-2 (no N addition, as a control), 4 g m-2 (4N) and 16 g m-2 (16N), which are equivalent to about 0-, 1- and 4-fold of the peak local N deposition. We measured flower rewards, flower morphology, flowering phenology, as well as pollinator visitation rate, fruit set and seed set by self- and outcross-fertilization of C. annuum. RESULTS: The four levels of N addition increased plant biomass, biomass allocation to flowers, flower size, stigma-anther separation, nectar production and pollen production, resulting in an increase in pollinator visitation and fruit set. Nevertheless, the control and 16 levels of N addition reduced plant biomass, biomass allocation to flowers, flower size and stigma-anther separation, and nectar and pollen production, and consequently decreased pollinator visitation and fruit set. Exclusion of pollinators and hand-pollination experiments revealed that low levels of N addition were associated with high seed set in outcrossed flowers; however, this trend was reversed in flowers grown in the control and 16N treatments. CONCLUSION: Our results suggest that an optimal level of 4N can enhance the correlation between flower traits, pollinator performance and plant reproduction. Our findings cast new light on the underlying mechanisms of plant-pollinator interactions and plant adaptation to nitrogen deposition.
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Capsicum , Néctar de las Plantas , Reproducción , Polinización , Plantas , Flores/anatomía & histologíaRESUMEN
BACKGROUND: Sleep disorders can profoundly affect neurological function. We investigated changes in social and anxiety-related brain functional connectivity induced by sleep deprivation, and the potential therapeutic effects of the general anaesthetics propofol and sevoflurane in rats. METHODS: Twelve-week-old male Sprague-Dawley rats were subjected to sleep deprivation for 20 h per day (from 14:00 to 10:00 the next day) for 4 consecutive weeks. They were free from sleep deprivation for the remaining 4 h during which they received propofol (40 mg kg-1 i.p.) or sevoflurane (2% for 2 h) per day or no treatment. These cohorts were instrumented for EEG/EMG recordings on days 2, 14, and 28. Different cohorts were used for open field and three-chambered social behavioural tests, functional MRI, nuclear magnetic resonance spectroscopy, and positron emission tomography imaging 48 h after 4 weeks of sleep deprivation. RESULTS: Propofol protected against sleep deprivation-induced anxiety behaviours with more time (44.7 [8.9] s vs 24.2 [4.1] s for the sleep-deprivation controls; P<0.001) spent in the central area of the open field test and improved social preference index by 30% (all P<0.01). Compared with the sleep-deprived rats, propofol treatment enhanced overall functional connectivity by 74% (P<0.05) and overall glucose metabolism by 30% (P<0.01), and improved glutamate kinetics by 20% (P<0.05). In contrast, these effects were not found after sevoflurane treatment. CONCLUSIONS: Unlike sevoflurane, propofol reduced sleep deprivation-induced social and anxiety-related behaviours. Propofol might be superior to sevoflurane for patients with sleep disorders who receive anaesthesia, which should be studied in clinical studies.
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Anestésicos por Inhalación , Ansiedad , Éteres Metílicos , Propofol , Privación de Sueño , Animales , Masculino , Ratas , Anestésicos por Inhalación/farmacología , Anestésicos Intravenosos/farmacología , Éteres Metílicos/farmacología , Propofol/farmacología , Ratas Sprague-Dawley , Sevoflurano/farmacología , Sueño , Conducta SocialRESUMEN
This research aimed to study the effect of Uremic Clearance Granules on chronic kidney disease in SD rats by using the methods of microbial functional genomics combined with metabolomics, and to preliminarily explore its mechanism. The SD rat model of chronic kidney disease was established by the adenine-induced method. After the model was successfully induced, the animals were randomly divided into a negative control group, a Uremic Clearance Granule treatment group, and a normal control group, with 8 rats in each group. After 4 weeks of administration, animal feces and serum were collected, and 16S rDNA sequencing technology was used to analyze the abundance, diversity, and function prediction of intestinal microorganisms. Liquid chromatography-mass spectrometry(LC-MS) technology was used to perform high-throughput sequencing to detect animal serum metabolites. The MetPA database was used to screen out potential biomarkers of chronic kidney disease in rats and conduct the enrichment analysis of metabolic pathways. Spearman's method was used to analyze the correlation between the two omics. The results showed that Uremic Clearance Granules effectively improved the body weight loss and renal function-related biochemical and appearance indicators in rats with chronic kidney disease. The results of 16S rDNA sequencing showed that Uremic Clearance Granules regulated the diversity and composition of the intestinal flora in rats with chronic kidney disease. The changes in the intestinal flora affected functional metabolic pathways such as amino acid biosynthesis and metabolism, lipid metabolism, and carbohydrate metabolism. The results of LC-MS showed that as compared with the negative control group, 15 metabolites were reversed in the Uremic Clearance Granule treatment group, among which 11 potential marker metabolites were significantly up-regulated and 4 potential marker metabolites were significantly down-regulated. Five amino acid metabolic pathways were mainly involved, which were significantly correlated with changes in the intestinal flora. Therefore, Uremic Clearance Granules can improve the renal function of rats with chronic kidney disease, and the mechanism may be related to its effect on the amino acid metabolism pathway by regulating the intestinal flora.
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Microbioma Gastrointestinal , Insuficiencia Renal Crónica , Ratas , Animales , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/tratamiento farmacológico , Metabolómica/métodos , AminoácidosRESUMEN
Objective: Methylated CpG binding protein 2 (MeCP2) is closely associated with heart failure, but its role in I/R injury remains unclear. The purpose of this study was to explore the role and underling mechanism of MeCP2 in myocardial I/R injury.Methods: Hypoxia/reperfusion (H/R)-induced H9c2 cardiomyocytes was used to establish an in vitro I/R injury model. Oxidative stress was assessed by measuring reactive oxygen species (ROS) generation, malondialdehyde (MDA) content and superoxide dismutase (SOD) activity. Cell viability and cell cycle arrest were evaluated by the Cell Counting Kit-8 assay and cell cycle assay, respectively. Apoptosis was determined using flow cytometry analysis.Results: The expression of MeCP2 in H9c2 cells was decreased after H/R treatment. The overexpression of MeCP2 inhibited H/R-induced oxidative stress, cell cycle arrest and apoptosis of H9c2 cells. Moreover, MeCP2 inhibited the activation of secreted frizzled related protein 4 (SFRP4)/Wnt/ß-catenin axis, and SFRP4 relieved the effect of MeCP2 on oxidative stress, cell cycle arrest and apoptosis in H/R-induced H9c2 cells.Conclusions: MeCP2 attenuated H/R-induced injury in H9c2 cardiomyocytes by modulating the SFRP4/Wnt/ß-catenin axis, which suggested that MeCP2 might serve as a therapeutic target of patients with AMI after reperfusion.
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Regulación de la Expresión Génica , Proteína 2 de Unión a Metil-CpG/genética , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas/genética , Vía de Señalización Wnt/genética , beta Catenina/genética , Animales , Apoptosis/genética , Western Blotting , Puntos de Control del Ciclo Celular/genética , Línea Celular , Hipoxia/fisiopatología , Malondialdehído/metabolismo , Proteína 2 de Unión a Metil-CpG/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/citología , Proteínas Proto-Oncogénicas/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxido Dismutasa/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: Hospices provide end-of-life care to patients who have complex health care needs and whose symptoms are difficult to control. Understanding why some hospices offer inpatient hospice care to patients could bring more evidence for policy makers and researchers to focus on the role of inpatient care in hospice. PURPOSE: The purpose of this study was to examine market and organizational factors that are associated with the provision of hospice inpatient care. METHODOLOGY: This study used a retrospective, longitudinal design (2009-2013). The study sample was drawn from three data resources: the Area Health Resources Files, the Provider of Services files, and Hospice Cost Reports from Centers for Medicare & Medicaid Services. The sample size was 2,391 hospices or 10,999 hospice observations over 5 years. A generalized linear mixed-effects model was used to examine the association between market and organizational factors and hospice inpatient services offering. RESULTS: On average, 94.59% of hospices offer inpatient services to patients. Proportion of adults who were over 65 years old (OR = 1.12) and Medicare-managed care penetration (OR = 1.02) were positively associated with the provision of hospice inpatient services. The number of hospitals with hospice program was negatively related to hospice inpatient services offering (OR = .95). Other factors such as nursing skill mix, volunteer dependence, and census region were also associated with inpatient services offering. PRACTICE IMPLICATIONS: The age demand of hospice care and Medicare-managed care penetration are related to hospice inpatient services offering. Hospices located in the market with more competition from hospitals that offer hospice program are less likely to offer inpatient care.
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Cuidados Paliativos al Final de la Vida , Hospitales para Enfermos Terminales , Adulto , Anciano , Humanos , Pacientes Internos , Medicare , Estudios Retrospectivos , Estados UnidosRESUMEN
BACKGROUND: Hospice performance is an overlooked area in the health care field due to the difficulty of measuring quality of care and the infrequent quality inspection. Based on the daily reimbursement mechanism for different levels of hospice care, inpatient services provision could influence both hospice-level length of stay (LOS) and financial performance. PURPOSE: The objective of this study was to explore the relationship between hospice inpatient services provision and hospice utilization and financial performance. METHODOLOGY/APPROACH: A longitudinal secondary data set (2009-2013) was merged from three sources: (a) Hospice Cost Reports from the Centers for Medicare & Medicaid Services, (b) the Provider of Services files, and (c) the Area Health Resources Files. The dependent variable in this study was hospice average LOS and financial performance measured by total operating margin (TOM) and return on assets. The independent variable was hospice inpatient services' offering. Mixed-effects regression models were used in the multivariate regression analyses. RESULTS: When comparing to hospices not providing inpatient services, offering inpatient services by staff was negatively related to average LOS (b = -0.063, p < .05) and TOM (b = -0.022, p < .05). The combination method with providing inpatient services by staff and under arrangement was negatively associated with return on assets (b = -0.073, p < .05). CONCLUSION: Hospice inpatient services provision was associated with average LOS and financial performance. PRACTICE IMPLICATIONS: Offering the inpatient services to patients by staff decreased average LOS and TOM. Hospice agencies may seek strategies to maintain their financial sustainability through outsourcing.
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Cuidados Paliativos al Final de la Vida , Hospitales para Enfermos Terminales , Anciano , Humanos , Pacientes Internos , Medicare , Mecanismo de Reembolso , Estados UnidosRESUMEN
The biological effects of extremely low-frequency electromagnetic fields (ELF-EMF) exposure are not fully clarified. We conducted this investigation to explore the effects of ELF-EMF on hematologic and biochemical indexes in adult rats. Thirty adult male Sprague-Dawley rats were exposed to ELF-EMF at 1 mT for 24 weeks, while another 30 SD rats were sham exposed. During the exposure, peripheral blood was collected every 4 weeks to analyze the hematologic parameters and biochemical indexes. The morphology of liver and kidney was detected by hematoxylin-eosin staining at the end of the experiment. Exposed to ELF-EMF at 1 mT did not exert any statistic difference on hematologic parameters including total white blood cell count, neutrophil ratio, lymphocyte ratio, red blood cells, hemoglobin concentration and platelets count, compared to the control group. Similarly, biochemical indexes, such as glucose, lipid profile, liver function and renal function, were not affected by ELF-EMF exposure. In addition, no morphological change was observed in the liver and kidney from the exposure group. The exposure to ELF-EMF at the intensity of 1 mT for 24 weeks did not affect hematologic and biochemical indexes in adult rats.
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Análisis Químico de la Sangre , Campos Electromagnéticos/efectos adversos , Animales , Riñón/metabolismo , Riñón/efectos de la radiación , Hígado/metabolismo , Hígado/efectos de la radiación , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Power-frequency electromagnetic fields (PF-EMFs) at 50 Hz are potential health risk factors. This study aimed to explore the effects of long-term exposure to 50-Hz PF-EMFs on general physiological conditions in Sprague-Dawley (SD) rats. During a 24-week exposure period, the body mass and water and food intake of the animals were recorded regularly. The hematologic parameters were detected every 12 weeks, and blood chemistry analyses were performed every 4 weeks. After sacrifice, morphology was identified by hematoxylin-eosin, Masson, and immunohistochemical staining. Fibrosis-related gene expression and oxidative stress status were also detected. Compared with the control group, exposure to 30, 100, or 500 µT PF-EMF did not exert any effect on body mass, food intake, or water intake. Similarly, no significant differences were found in hematologic parameters or blood chemistry analyses among these groups. Furthermore, morphological assays showed that exposure to PF-EMFs had no influence on the structure of the liver or kidney. Finally, fibrosis-related gene expression and oxidative stress status were unaltered by PF-EMF exposure. The present study indicates that 24 weeks of exposure to PF-EMFs at intensities of 30, 100, or 500 µT might not affect hemograms, blood chemistry, fibrosis, or oxidative stress in the liver or kidney in SD rats. © 2020 Bioelectromagnetics Society.
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Análisis Químico de la Sangre , Campos Electromagnéticos/efectos adversos , Riñón/patología , Riñón/efectos de la radiación , Cirrosis Hepática/etiología , Estrés Oxidativo/efectos de la radiación , Animales , Regulación de la Expresión Génica/efectos de la radiación , Pruebas Hematológicas , Riñón/metabolismo , Cirrosis Hepática/sangre , Cirrosis Hepática/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Hospice is the key provider of end-of-life care to patients. As the number of U.S. hospice agencies has rapidly increased, the performance has been scrutinized more deeply. PURPOSE: To foster understanding of how hospice performance is measured and what factors are associated with performance, we conducted a systematic review of empirical research on hospice performance in the United States. METHODS: Both structure-process-outcome and structure-conduct-performance frameworks were applied to categorize and summarize the hospice performance literature. A total of 36 studies were included in the systematic review. RESULTS: Hospice agencies adopted different strategies (e.g., service provision strategy and staffing strategy) to improve performance. Two strategic approaches (innovation and volunteer usage) were associated with better outcomes. Hospice organizational factors, market environment, and patient characteristics were related to hospice strategic conduct and performance. Majority of hospice performance studies have examined the relationship between hospice structure and strategic conduct/process, with fewer studies focusing on structure performance and even fewer concentrating on strategy performance. PRACTICE IMPLICATIONS: Patient, organizational, and market factors are associated with hospice strategic conduct and performance. The majority of the literature considered the impact of hospice organizational characteristics, whereas only a few studies included patient and market factors. The summarization of factors that may influence hospice performance provides insight to different stakeholders.
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Cuidados Paliativos al Final de la Vida/psicología , Objetivos Organizacionales , Publicaciones Periódicas como Asunto , Cuidado Terminal/normas , Cuidados Paliativos al Final de la Vida/organización & administración , Humanos , Evaluación del Resultado de la Atención al Paciente , Estados UnidosRESUMEN
BACKGROUND: Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca2+ handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca 2+ overload. In this study, we investigated the effects of ranolazine on pressure overload-induced cardiac hypertrophy and heart failure in mice. METHODS AND RESULTS: Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca2+ imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca 2+ release and increased SR Ca 2+ leak. Ranolazine restored aberrant SR Ca 2+ handling induced by pressure overload. Ranolazine also suppressed Na + overload induced in the failing heart, and restored Na + -induced Ca 2+ overload in an sodium-calcium exchanger (NCX)-dependent manner. Ranolazine suppressed the Ca 2+ -dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor-2 (MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T-cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER-initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER-initiated cardiomyocyte apoptosis. CONCLUSIONS: Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload-induced cardiac hypertrophy and systolic and diastolic function by restoring Na+ and Ca 2+ handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure.
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Calcio/metabolismo , Cardiomegalia/prevención & control , Fármacos Cardiovasculares/uso terapéutico , Insuficiencia Cardíaca/prevención & control , Ranolazina/uso terapéutico , Sodio/metabolismo , Animales , Fármacos Cardiovasculares/farmacología , Línea Celular , Fibrosis/prevención & control , Hipertensión/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Distribución Aleatoria , Ranolazina/farmacologíaRESUMEN
BACKGROUND: Metabolic abnormalities have been implicated as a causal event in diabetic cardiomyopathy (DCM). However, the mechanisms underlying cardiac metabolic disorder in DCM were not fully understood. RESULTS: Db/db mice, palmitate treated H9c2 cells and primary neonatal rat cardiomyocytes were employed in the current study. Microarray data analysis revealed that PGC-1ß may play an important role in DCM. Downregulation of PGC-1ß relieved palmitate induced cardiac metabolism shift to fatty acids use and relevant lipotoxicity in vitro. Bioinformatics coupled with biochemical validation was used to confirm that PGC-1ß was one of the direct targets of miR-30c. Remarkably, overexpression of miR-30c by rAAV system improved glucose utilization, reduced excessive reactive oxygen species production and myocardial lipid accumulation, and subsequently attenuated cardiomyocyte apoptosis and cardiac dysfunction in db/db mice. Similar effects were also observed in cultured cells. More importantly, miR-30c overexpression as well as PGC-1ß knockdown reduced the transcriptional activity of PPARα, and the effects of miR-30c on PPARα was almost abated by PGC-1ß knockdown. CONCLUSIONS: Our data demonstrated a protective role of miR-30c in cardiac metabolism in diabetes via targeting PGC-1ß, and suggested that modulation of PGC-1ß by miR-30c may provide a therapeutic approach for DCM.
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Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Cardiomiopatías Diabéticas/prevención & control , MicroARNs/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , Coactivadores de Receptor Nuclear/metabolismo , PPAR alfa/metabolismo , Factores de Transcripción/metabolismo , Animales , Apoptosis , Línea Celular , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Regulación de la Expresión Génica , Metabolismo de los Lípidos , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , Miocitos Cardíacos/ultraestructura , Proteínas Nucleares/genética , Coactivadores de Receptor Nuclear/genética , Estrés Oxidativo , PPAR alfa/genética , Ratas , Transducción de Señal , Factores de Transcripción/genéticaRESUMEN
In the present study, the effects of power-frequency magnetic fields (PF-MF) on fertility and development were investigated in rats and mice. Adult Sprague-Dawley rats and C57BL/6J mice were divided into four groups: a sham exposure group and 30-µT, 100-µT and 500-µT PF-MF exposure groups. The rats were exposed for 24 weeks, and the exposure time for mice ranged from 18 d to 12 weeks, dependent on the different investigated end points. The rats and mice were exposed for 20 h/d. Plasma hormone levels in rats and mice were analyzed. Furthermore, pregnancy rates and implanted embryos were recorded in pregnant mice. Finally, the neonatal growth of mice was evaluated. The results showed that none of the three intensities affected the body weight and paired ovary weight in female rats. Meanwhile, none of the three intensities affected the body weight, weights of paired testes, weights of paired epididymis and sperm count in male rats. Similarly, no significant differences were found in plasma sex hormone levels between the different PF-MF exposure groups and the sham exposure group. In addition, the pregnancy rates and implanted embryos were not significantly different between the four groups. Moreover, PF-MF exposures had no effects on either the number of fetuses in pregnant mice or the growth and development of neonatal mice.
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Fertilidad , Crecimiento y Desarrollo , Animales , Peso Corporal , Femenino , Feto/fisiología , Hormonas Esteroides Gonadales/sangre , Masculino , Ratones , Tamaño de los Órganos , Embarazo , Índice de Embarazo , Ratas , Ratas Sprague-Dawley , Reproducción , Recuento de Espermatozoides , Supervivencia TisularRESUMEN
As the world's second largest sand sea and one of the most important dust sources to the global aerosol system, the formation of the Taklimakan Desert marks a major environmental event in central Asia during the Cenozoic. Determining when and how the desert formed holds the key to better understanding the tectonic-climatic linkage in this critical region. However, the age of the Taklimakan remains controversial, with the dominant view being from â¼ 3.4 Ma to â¼ 7 Ma based on magnetostratigraphy of sedimentary sequences within and along the margins of the desert. In this study, we applied radioisotopic methods to precisely date a volcanic tuff preserved in the stratigraphy. We constrained the initial desertification to be late Oligocene to early Miocene, between â¼ 26.7 Ma and 22.6 Ma. We suggest that the Taklimakan Desert was formed as a response to a combination of widespread regional aridification and increased erosion in the surrounding mountain fronts, both of which are closely linked to the tectonic uplift of the Tibetan-Pamir Plateau and Tian Shan, which had reached a climatically sensitive threshold at this time.
RESUMEN
The development of fluvial systems in East Asia is closely linked to the evolving topography following India-Eurasia collision. Despite this, the age of the Yangtze River system has been strongly debated, with estimates ranging from 40 to 45 Ma, to a more recent initiation around 2 Ma. Here, we present (40)Ar/(39)Ar ages from basalts interbedded with fluvial sediments from the lower reaches of the Yangtze together with detrital zircon U-Pb ages from sand grains within these sediments. We show that a river containing sediments indistinguishable from the modern river was established before ~23 Ma. We argue that the connection through the Three Gorges must postdate 36.5 Ma because of evaporite and lacustrine sedimentation in the Jianghan Basin before that time. We propose that the present Yangtze River system formed in response to regional extension throughout eastern China, synchronous with the start of strike-slip tectonism and surface uplift in eastern Tibet and fed by strengthened rains caused by the newly intensified summer monsoon.
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Flavonoids exhibit a broad range of biological activities including antibacterial activity. However, the mechanism of their antibacterial activity has not been fully investigated. The antibacterial activity and membrane interaction of 11 flavonoids (including 2 polymethoxyflavones and 4 isoflavonoids) against Escherichia coli were examined in this study. The antibacterial capacity was determined as flavonoids>polymethoxyflavones>isoflavonoids. Using fluorescence, it was observed that the 5 flavonoids rigidified the liposomal membrane, while the polymethoxyflavones and isoflavonoids increased membrane fluidity. There was a significant positive correlation between antibacterial capacity and membrane rigidification effect of the flavonoids. A quantitative structure-activity relationship (QSAR) study demonstrated that the activity of the flavonoid compounds can be related to molecular hydrophobicity (CLogP) and charges on C atom at position3 (C3). The QSAR model could be used to predict the antibacterial activity of flavonoids which could lead to natural compounds having important use in food and medical industry.
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Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Flavonoides/farmacología , Antibacterianos/química , Membrana Celular/efectos de los fármacos , Flavonoides/química , Relación Estructura-Actividad Cuantitativa , Espectrometría de FluorescenciaRESUMEN
Tumor hypoxia impairs the generation of reactive oxygen species and the induction of immunogenic cell death (ICD) for photodynamic therapy (PDT), thus impeding its efficacy and the subsequent immunotherapy. In addition, hypoxia plays a critical role in forming immunosuppressive tumor microenvironments (TME) by regulating the infiltration of immunosuppressive tumor-associated macrophages (TAMs) and the expression of programmed death ligand 1 (PD-L1). To simultaneously tackle these issues, a MnO2-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. The MnO2-catalyzed oxygen supply bolsters the efficacy of PDT and PTX-mediated chemotherapy, collectively amplifying the induction of ICD and the expansion of tumor-specific cytotoxic T lymphocytes (CTLs). More importantly, hypoxia releif reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint blockade (ICB) by NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.
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Antígeno B7-H1 , Neoplasias , Humanos , Compuestos de Manganeso , Microambiente Tumoral , Óxidos , Inmunoterapia , Inmunosupresores , Hipoxia , Neoplasias/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Introduction: Humanization is typically adopted to reduce the immunogenicity of murine antibodies generated by hybridoma technology when used in humans. Methods: Two different strategies of antibody humanization are popularly employed, including "complementarity determining region (CDR) grafting" and "framework (FR) shuffling" to humanize a murine antibody against human programmed death-1 (PD-1), XM PD1. In CDR-grafting humanization, the CDRs of XM PD-1, were grafted into the human FR regions with high homology to the murine FR counterparts, and back mutations of key residues were performed to retain the antigen-binding affinities. While in FR-shuffling humanization, a combinatorial library of the six murine CDRs in-frame of XM PD-1 was constructed to a pool of human germline FRs for high-throughput screening for the most favorable variants. We evaluated many aspects which were important during antibody development of the molecules obtained by the two methods, including antibody purity, thermal stability, binding efficacy, predicted humanness, and immunogenicity, along with T cell epitope prediction for the humanized antibodies. Results: While the ideal molecule was not achieved through CDR grafting in this particular instance, FR-shuffling proved successful in identifying a suitable candidate. The study highlights FR-shuffling as an effective complementary approach that potentially increases the success rate of antibody humanization. It is particularly noted for its accessibility to those with a biological rather than a computational background. Discussion: The insights from this comparison are intended to assist other researchers in selecting appropriate humanization strategies for drug development, contributing to broader application and understanding in the field.
Asunto(s)
Regiones Determinantes de Complementariedad , Receptor de Muerte Celular Programada 1 , Animales , Humanos , Ratones , Receptor de Muerte Celular Programada 1/inmunología , Regiones Determinantes de Complementariedad/inmunología , Regiones Determinantes de Complementariedad/genética , Anticuerpos Monoclonales Humanizados/inmunología , Epítopos de Linfocito T/inmunologíaRESUMEN
Background: The neurobiological basis of gaining consciousness from unconscious state induced by anesthetics remains unknown. This study was designed to investigate the involvement of the cerebello-thalamus-motor cortical loop mediating consciousness transitions from the loss of consciousness (LOC) induced by an inhalational anesthetic sevoflurane in mice. Methods: The neural tracing and fMRI together with opto-chemogenetic manipulation were used to investigate the potential link among cerebello-thalamus-motor cortical brain regions. The fiber photometry of calcium and neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA) and norepinephrine (NE), were monitored from the motor cortex (M1) and the 5th lobule of the cerebellar vermis (5Cb) during unconsciousness induced by sevoflurane and gaining consciousness after sevoflurane exposure. Cerebellar Purkinje cells were optogenetically manipulated to investigate their influence on consciousness transitions during and after sevoflurane exposure. Results: Activation of 5Cb Purkinje cells increased the Ca2+ flux in the M1 CaMKIIα+ neurons, but this increment was significantly reduced by inactivation of posterior and parafascicular thalamic nucleus. The 5Cb and M1 exhibited concerted calcium flux, and glutamate and GABA release during transitions from wakefulness, loss of consciousness, burst suppression to conscious recovery. Ca2+ flux and Glu release in the M1, but not in the 5Cb, showed a strong synchronization with the EEG burst suppression, particularly, in the gamma-band range. In contrast, the Glu, GABA and NE release and Ca2+ oscillations were coherent with the EEG gamma band activity only in the 5Cb during the pre-recovery of consciousness period. The optogenetic activation of Purkinje cells during burst suppression significantly facilitated emergence from anesthesia while the optogenetic inhibition prolonged the time to gaining consciousness. Conclusions: Our data indicate that cerebellar neuronal communication integrated with motor cortex through thalamus promotes consciousness recovery from anesthesia which may likely serve as arousal regulation.