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Plant inflorescence architecture is determined by inflorescence meristem (IM) activity and controlled by genetic mechanisms associated with environmental factors. In Arabidopsis (Arabidopsis thaliana), TERMINAL FLOWER1 (TFL1) is expressed in the IM and is required to maintain indeterminate growth, whereas LEAFY (LFY) is expressed in the floral meristems (FMs) formed at the periphery of the IM and is required to activate determinate floral development. Here, we address how Arabidopsis indeterminate inflorescence growth is determined. We show that the 26S proteasome subunit REGULATORY PARTICLE AAA-ATPASE 2a (RPT2a) is required to maintain the indeterminate inflorescence architecture in Arabidopsis. rpt2a mutants display reduced TFL1 expression levels and ectopic LFY expression in the IM and develop a determinate zigzag-shaped inflorescence. We further found that RPT2a promotes DNA METHYLTRANSFERASE1 degradation, leading to DNA hypomethylation upstream of TFL1 and high TFL1 expression levels in the wild-type IM. Overall, our work reveals that proteolytic input into the epigenetic regulation of TFL1 expression directs inflorescence architecture in Arabidopsis, adding an additional layer to stem cell regulation.
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The failure of apoptotic cell clearance is linked to autoimmune diseases, nonresolving inflammation, and developmental abnormalities; however, pathways that regulate phagocytes for efficient apoptotic cell clearance remain poorly known. Apoptotic cells release find-me signals to recruit phagocytes to initiate their clearance. Here we found that find-me signal sphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO) signaling promoted apoptotic cell clearance and immune tolerance. Dying cell-released S1P activated macrophage EPO signaling. Erythropoietin receptor (EPOR)-deficient macrophages exhibited impaired apoptotic cell phagocytosis. EPO enhanced apoptotic cell clearance through peroxisome proliferator activated receptor-γ (PPARγ). Moreover, macrophage-specific Epor(-/-) mice developed lupus-like symptoms, and interference in EPO signaling ameliorated the disease progression in lupus-like mice. Thus, we have identified a pathway that regulates macrophages to clear dying cells, uncovered the priming function of find-me signal S1P, and found a role of the erythropoiesis regulator EPO in apoptotic cell disposal, with implications for harnessing dying cell clearance.
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Eritropoyetina/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lisofosfolípidos/metabolismo , Macrófagos/fisiología , Receptores de Eritropoyetina/metabolismo , Esfingosina/análogos & derivados , Animales , Apoptosis , Línea Celular , Femenino , Tolerancia Inmunológica/genética , Lisofosfolípidos/genética , Activación de Macrófagos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR gamma/genética , PPAR gamma/metabolismo , Comunicación Paracrina , Fagocitosis/genética , Receptores de Eritropoyetina/genética , Transducción de Señal , Esfingosina/genética , Esfingosina/metabolismoRESUMEN
Renewal of integumentary organs occurs cyclically throughout an organism's lifetime, but the mechanism that initiates each cycle remains largely unknown. In a miniature pig model of tooth development that resembles tooth development in humans, the permanent tooth did not begin transitioning from the resting to the initiation stage until the deciduous tooth began to erupt. This eruption released the accumulated mechanical stress inside the mandible. Mechanical stress prevented permanent tooth development by regulating expression and activity of the integrin ß1-ERK1-RUNX2 axis in the surrounding mesenchyme. We observed similar molecular expression patterns in human tooth germs. Importantly, the release of biomechanical stress induced downregulation of RUNX2-wingless/integrated (Wnt) signaling in the mesenchyme between the deciduous and permanent tooth and upregulation of Wnt signaling in the epithelium of the permanent tooth, triggering initiation of its development. Consequently, our findings identified biomechanical stress-associated Wnt modulation as a critical initiator of organ renewal, possibly shedding light on the mechanisms of integumentary organ regeneration.
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Regulación hacia Abajo , Odontogénesis , Vía de Señalización Wnt , Animales , Fenómenos Biomecánicos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Saco Dental/citología , Saco Dental/metabolismo , Humanos , Integrina beta1/metabolismo , Modelos Biológicos , Cultivo Primario de Células , Porcinos , Porcinos EnanosRESUMEN
Determination of tipping points in nitrogen (N) isotope (δ15N) natural abundance, especially soil δ15N, with increasing aridity, is critical for estimating N-cycling dynamics and N limitation in terrestrial ecosystems. However, whether there are linear or nonlinear responses of soil δ15N to increases in aridity and if these responses correspond well with soil N cycling remains largely unknown. In this study, we investigated soil δ15N and soil N-cycling characteristics in both topsoil and subsoil layers along a drought gradient across a 3000-km transect of drylands on the Qinghai-Tibetan Plateau. We found that the effect of increasing aridity on soil δ15N values shifted from negative to positive with thresholds at aridity index (AI) = 0.27 and 0.29 for the topsoil and subsoil, respectively, although soil N pools and N transformation rates linearly decreased with increasing aridity in both soil layers. Furthermore, we identified markedly different correlations between soil δ15N and soil N-cycling traits above and below the AI thresholds (0.27 and 0.29 for topsoil and subsoil, respectively). Specifically, in wetter regions, soil δ15N positively correlated with most soil N-cycling traits, suggesting that high soil δ15N may result from the "openness" of soil N cycling. Conversely, in drier regions, soil δ15N showed insignificant relationships with soil N-cycling traits and correlated well with factors, such as soil-available phosphorus and foliage δ15N, demonstrating that pathways other than typical soil N cycling may dominate soil δ15N under drier conditions. Overall, these results highlight that different ecosystem N-cycling processes may drive soil δ15N along the aridity gradient, broadening our understanding of N cycling as indicated by soil δ15N under changing drought regimes. The aridity threshold of soil δ15N should be considered in terrestrial N-cycling models when incorporating 15N isotope signals to predict N cycling and availability under climatic dryness.
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Sequías , Ecosistema , Ciclo del Nitrógeno , Isótopos de Nitrógeno , Suelo , Suelo/química , Isótopos de Nitrógeno/análisis , China , Nitrógeno/análisis , Nitrógeno/metabolismo , Clima DesérticoRESUMEN
Sodium/potassium-ion batteries (NIBs and KIBs) are considered the most promising candidates for lithium-ion batteries in energy storage fields. Tin sulfide (SnS2) is regarded as an attractive negative candidate for NIBs and KIBs thanks to its superior power density, high-rate performance and natural richness. Nevertheless, the slow dynamics, the enormous volume change and the decomposition of polysulfide intermediates limit its practical application. Herein, microcubes SnS2 were prepared through sacrificial MnCO3 template-assisted and a facile solvothermal reaction strategy and their performance was investigated in Na and K-based cells. The unique hollow cubic structure and well-confined SnS2 nanosheets play an important role in Na+/K+ rapid kinetic and alleviating volume change. The effect of the carbon additives (Super P/C65) on the electrochemical properties were investigated thoroughly. The in operando and ex-situ characterization provide a piece of direct evidence to clarify the storage mechanism of such conversion-alloying type negative electrode materials.
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The intestinal tract, which is the primary site of digestion and absorption of nutrients, is one of the most vulnerable organs during aging. Dietary nitrate, which is mainly derived from the diet and absorbed in the intestinal tract, is a key messenger that connecting oral and general health. However, whether dietary nitrate regulates intestinal tract homeostasis remains unclear. Our data revealed that the serum and salivary nitrate levels decreased during mice aging. The functional proteins of the epithelial barrier (E-cadherin, Claudin-1 and Zonula Occludens-1) in the colon tissues decreased during the aging process. Long-term nitrate supplement in drinking water restored the serum and salivary nitrate levels and increased the functional proteins expression of the colon epithelial barrier. Dietary nitrates increase the relative abundance of some intestinal probiotics, particularly those associated with the production of short-chain fatty acids, such as Blautia, Alloprevotella, Butyricicoccus, and Ruminococcaceae, while promoting the butyric acid production in the colon. Moreover, the expression of Sialin (encoded by Slc17a5), which is a nitrate transporter, increased in the colon epithelial cells by nitrate supplementation. The epithelial cell-conditional Slc17a5-knockout mutant mice (K14-cre; Slc17a5fl/fl) revealed that the functional proteins expression of the colon epithelial barrier and the proliferation of PCNA-positive intestinal epithelial cells in the colon crypts was significantly decreased compared with those of the K14-cre; Slc17a5fl/+ mice. Taken together, our findings suggested that nitrate supplementations were associated with the increased expression of colonic epithelial barriers-related proteins and the increased Sialin expression. Nitrate may serve as a potential therapeutic approach in maintaining aged colonic homeostasis.
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In this study, we outline a general method for the construction of various (furyl)methyl disulfides from acetyl-masked disulfide nucleophiles and ene-yne-ketones. This protocol is feathered by metal-free, simple experimental conditions, high efficiency, and scalable potential, which make it attractive and practical.
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Under transition-metal-free conditions, trisulfide dioxides were used as disulfurating reagents to react with a wide range of amides, affording various substituted N-disulfanyl amides in good yields. Furthermore, the gram-scale experiment has confirmed the practicability of this approach.
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2,6-Dichlorobenzamide (BAM) is an omnipresent micropollutant in European groundwaters. Aminobacter niigataensis MSH1 is a prime candidate for biologically treating BAM-contaminated groundwater since this organism is capable of utilizing BAM as a carbon and energy source. However, detailed information on the BAM degradation kinetics by MSH1 at trace concentrations is lacking, while this knowledge is required for predicting and optimizing the degradation process. Contaminating assimilable organic carbon (AOC) in media makes the biodegradation experiment a mixed-substrate assay and hampers exploration of pollutant degradation at trace concentrations. In this study, we examined how the BAM concentration affects MSH1 growth and BAM substrate utilization kinetics in a AOC-restricted background to avoid mixed-substrate conditions. Conventional Monod kinetic models were unable to predict kinetic parameters at low concentrations from kinetics determined at high concentrations. Growth yields on BAM were concentration-dependent and decreased substantially at trace concentrations; i.e., growth of MSH1 diminished until undetectable levels at BAM concentrations below 217 µg-C/L. Nevertheless, BAM degradation continued. Decreasing growth yields at lower BAM concentrations might relate to physiological adaptations to low substrate availability or decreased expression of downstream steps of the BAM catabolic pathway beyond 2,6-dichlorobenzoic acid (2,6-DCBA) that ultimately leads to Krebs cycle intermediates for growth and energy conservation.
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Benzamidas , Carbono , Phyllobacteriaceae , Biodegradación Ambiental , Benzamidas/metabolismo , Carbono/metabolismoRESUMEN
BACKGROUND: To investigate the incidence of depression in middle-aged and elderly patients with diabetes in China and the influencing factors to provide a theoretical basis to improve the mental health of middle-aged and elderly patients with diabetes and formulate prevention, control, and intervention strategies. METHODS: The sample of this study was obtained from the China Health and Aging Tracking Survey (CHARLS) 2018 survey data, and middle-aged and older patients with diabetes(responding "Yes" to the questionnaire: "Have you ever been told by a doctor that you have diabetes or elevated blood glucose [including abnormal glucose tolerance and elevated fasting glucose]?") aged ≥ 45 years were selected as study subjects (n = 2,613 ). Depressive symptoms of the study subjects were determined using the simplified version of the Depression Scale for Epidemiological Surveys scores(a score ≥ 10 was defined as depression), influence factors were analyzed using binary logistic regression, and proportion of depressive symptoms was standardized using the sex ratio of the seventh census. RESULTS: Among the 2,613 middle-aged and elderly patients with diabetes, 1782 (68.2%) had depressive symptoms and 831 (31.8%) had no depressive symptoms. There were 481 (27.0%) patients aged 45-59 years, 978 (54.9%) aged 60-74 years, and 323 (18.1%) aged ≥ 75 years. The depression rate among middle-aged and elderly Chinese patients with diabetes after standardization correction was 67.5%. Binary logistic regression results showed that age, education level, life satisfaction, marital satisfaction, self-rated health grade, somatic pain, visual impairment, physical disability, and the presence of comorbid chronic diseases were factors that influenced the onset of depression in middle-aged and elderly Chinese patients with diabetes (P < 0.05). CONCLUSION: According to a survey analysis of the CHARLS 2018 data, depression is influenced by a combination of factors among middle-aged and elderly patients with diabetes in China. Therefore, for this population, targeted prevention and control should be carried out for key populations, such as middle-aged and elderly people, poor physical health, and low life satisfaction and marital satisfaction, from various dimensions (e.g., demographic and sociological factors, physical health status, and life satisfaction and marital satisfaction).
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Depresión , Diabetes Mellitus , Anciano , Persona de Mediana Edad , Humanos , Depresión/epidemiología , Depresión/psicología , Incidencia , Diabetes Mellitus/epidemiología , Envejecimiento , Glucosa , China/epidemiología , Estudios LongitudinalesRESUMEN
Epithelial-mesenchymal interactions occur during tooth development. The dental epithelium (DE) is regarded as the signal center that regulates tooth morphology. However, the mechanism by which DE regulates the differentiation of mesenchyme-derived dental papilla (DP) into odontoblasts remains unclear. Using miniature pigs as a model, we analyzed the expression profiles of the DE and DP during odontoblast differentiation using high-throughput RNA sequencing. The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is one of the most enriched pathways in both DE and DP. The PI3K/AKT pathway was first activated in the inner enamel epithelium but not in the DP on embryonic day 50. This pathway was then activated in the odontoblast layer on embryonic day 60. We showed that AKT activation promoted odontoblast differentiation of DP cells. We further demonstrated that activation of PI3K/AKT signaling in the DE effectively increased the expression levels of AKT and dentin sialophosphoprotein in DP cells. Additionally, we found that DE cells secreted collagen type IV alpha 6 chain (COL4A6) downstream of epithelial AKT signaling to positively regulate mesenchymal AKT levels. Therefore, our data suggest that PI3K/AKT signaling from the DE to the DP promotes odontoblast differentiation via COL4A6 secretion.
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Odontoblastos , Proteínas Proto-Oncogénicas c-akt , Animales , Porcinos , Odontoblastos/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Diferenciación Celular/genética , EpitelioRESUMEN
OBJECTIVE: To evaluate the long-term outcomes of standard endovascular aneurysm repair (S-EVAR) of juxtarenal abdominal aortic aneurysms (JAAAs). METHODS: Data of patients with JAAAs who were unsuitable for fenestrated endovascular aneurysm repair (F-EVAR) and open repair (OR) and underwent treatment from January 2015 to December 2021 were retrospectively reviewed. Computed tomography angiography and ultrasonography of the aorta were performed before discharge, at 6 and 12 months postoperatively, and annually thereafter. The main outcome measures were mortality, type Ia endoleaks, and reintervention. RESULTS: A total of 62 patients (mean age, 72.1 ± 7.3 years) underwent S-EVAR. The mean aneurysm length and diameter and the proximal neck length and diameter were 110.4 ± 30.9 mm, 57.2 ± 15.9 mm, 8.09 ± 0.97 mm, and 26.05 ± 0.49 mm, respectively. The mean suprarenal and infrarenal aortic angles were 162.9 ± 26° and 144.1 ± 31°, respectively. The mean follow-up duration was 40.6 ± 23.4 months and the 5-year survival rate was 62.2%. Six (9.8%) patients experienced type Ia endoleaks, of whom three underwent endovascular repair at 12, 18, and 24 months, one underwent conversion to OR for AAA rupture at 7 days and died, two had minor endoleaks and were kept under observation, and one declined reintervention at 36 months. The 5-year freedom from reintervention rate was 84.4%. The aneurysm diameter shrank in 50 cases (81%), remained stable in 5 cases (8%), and increased in 7 cases (11.3%). A suprarenal aortic angle <114° was associated with type Ia endoleak (p = .005). CONCLUSIONS: In patients unsuitable for F-EVAR and OR and with a suprarenal aortic angle >114°, the use of S-EVAR for JAAAs can be considered safe and effective. In this study, early and long-term postoperative outcomes demonstrated that S-EVAR achieved satisfactory results in the prevention of aneurysm rupture and associated mortality.
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INTRODUCTION: Exercise enhances one's health and competitiveness. A strong physical fitness status can pave the way for a promising future. This study presents the time-based trends in physical fitness indicators-including height, weight, BMI, lung capacity, dash, long-distance running, and standing long jump-among medical undergraduates during their university years. Additionally, we analyzed the impact of students' physical fitness on their career paths. METHOD: We conducted a retrospective database study by collecting physical fitness test data and career paths information for 634 medical students from a university in southwestern China. These students graduated in 2022. The career paths included pursuits in further studies, employment, and unemployment. To detect differences in these aspects, we used the t-test and Chi-square test. RESULTS: Our study indicates a significant declining trend in the physical fitness of medical students during their university years. The changes observed between the first and fourth tests are as follows: Weight (kg): 58.52 ± 10.48 to 60.73 ± 12.07, P < 0.00 BMI (kg/m^2): 20.79 ± 2.74 to 21.24 ± 3.06, P < 0.00 50-m dash (s): 8.91 ± 0.99 to 9.25 ± 1.11, P < 0.00 Standing long jump (cm): 187.74 ± 30.98 to 182.59 ± 32.25, P < 0.00 800-m run for females (min): 3.84 ± 0.47 to 4.48 ± 0.85, P < 0.00 1000-m run for males (min): 3.98 ± 0.63 to 4.62 ± 0.87, P < 0.00 Sit-ups for females (count): 30.39 ± 7.5 to 29.03 ± 8.82, P < 0.00 Upon analyzing the correlation between changes in physical fitness and career paths, students with stable or decreased BMI had better post-graduation outcomes compared to students with increased BMI. CONCLUSIONS: Medical students show a declining trend in physical fitness during their undergraduate years. A good physical health status is beneficial for achieving better career paths. Medical students should place greater emphasis on physical exercise during their time in school.
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Aptitud Física , Estudiantes de Medicina , Humanos , Masculino , Femenino , Estudios Longitudinales , Estudios Retrospectivos , China , Adulto Joven , Selección de Profesión , Adulto , Índice de Masa Corporal , Educación de Pregrado en MedicinaRESUMEN
Recent studies on watermarking techniques based on image carriers have demonstrated new approaches that combine adversarial perturbations against steganalysis with embedding distortions. However, while these methods successfully counter convolutional neural network-based steganalysis, they do not adequately protect the data of the carrier itself. Recognizing the high sensitivity of Deep Neural Networks (DNNs) to small perturbations, we propose HAG-NET, a method based on image carriers, which is jointly trained by the encoder, decoder, and attacker. In this paper, the encoder generates Adversarial Steganographic Examples (ASEs) that are adversarial to the target classification network, thereby providing protection for the carrier data. Additionally, the decoder can recover secret data from ASEs. The experimental results demonstrate that ASEs produced by HAG-NET achieve an average success rate of over 99% on both the MNIST and CIFAR-10 datasets. ASEs generated with the attacker exhibit greater robustness in terms of attack ability, with an average increase of about 3.32%. Furthermore, our method, when compared with other generative stego examples under similar perturbation strength, contains significantly more information according to image information entropy measurements.
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The responses of soil nitrogen (N) transformations to climate change are crucial for biome productivity prediction under global change. However, little is known about the responses of soil gross N transformation rates to drought gradient. Along an aridity gradient across the 2700 km transect of drylands on the Qinghai-Tibetan Plateau, this study measured three main soil gross N transformation rates in both topsoil (0-10 cm) and subsoil (20-30 cm) using the laboratorial 15 N labeling. The relevant soil abiotic and biotic variables were also determined. The results showed that gross N mineralization and nitrification rates steeply decreased with increasing aridity when aridity was less than 0.5 but just slightly decreased with increasing aridity when aridity was larger than 0.5 at both soil layers. In topsoil, the decreases of the two gross rates were accompanied by the similar decreased patterns of soil total N content and microbial biomass carbon with increasing aridity (p < .05). In subsoil, although the decreased pattern of soil total N with increasing aridity was still similar to the decreases of the two gross rates (p < .05), microbial biomass carbon did not change (p > .05). Instead, bacteria and ammonia oxidizing archaea abundances decreased with increasing aridity when aridity was larger than 0.5 (p < .05). With an aridity threshold of 0.6, gross N immobilization rate increased with increasing aridity in wetter region (aridity < 0.6) accompanied with an increased bacteria/fungi ratio, but decreased with increasing aridity in drier region (aridity > 0.6) where mineral N and microbial biomass N also decreased at both soil layers (p < .05). This study provided new insight to understand the differential responses of soil N transformation to drought gradient. The threshold responses of the gross N transformation rates to aridity gradient should be noted in biogeochemical models to better predict N cycling and manage land in the context of global change.
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Nitrógeno , Suelo , Suelo/química , Nitrógeno/análisis , Ecosistema , Nitrificación , Bacterias , Microbiología del Suelo , CarbonoRESUMEN
Microbial necromass is a large and persistent component of soil organic carbon (SOC), especially under croplands. The effects of cropland management on microbial necromass accumulation and its contribution to SOC have been measured in individual studies but have not yet been summarized on the global scale. We conducted a meta-analysis of 481-paired measurements from cropland soils to examine the management effects on microbial necromass and identify the optimal conditions for its accumulation. Nitrogen fertilization increased total microbial necromass C by 12%, cover crops by 14%, no or reduced tillage (NT/RT) by 20%, manure by 21%, and straw amendment by 21%. Microbial necromass accumulation was independent of biochar addition. NT/RT and straw amendment increased fungal necromass and its contribution to SOC more than bacterial necromass. Manure increased bacterial necromass higher than fungal, leading to decreased ratio of fungal-to-bacterial necromass. Greater microbial necromass increases after straw amendments were common under semi-arid and in cool climates in soils with pH <8, and were proportional to the amount of straw input. In contrast, NT/RT increased microbial necromass mainly under warm and humid climates. Manure application increased microbial necromass irrespective of soil properties and climate. Management effects were especially strong when applied during medium (3-10 years) to long (10+ years) periods to soils with larger initial SOC contents, but were absent in sandy soils. Close positive links between microbial biomass, necromass and SOC indicate the important role of stabilized microbial products for C accrual. Microbial necromass contribution to SOC increment (accumulation efficiency) under NT/RT, cover crops, manure and straw amendment ranged from 45% to 52%, which was 9%-16% larger than under N fertilization. In summary, long-term cropland management increases SOC by enhancing microbial necromass accumulation, and optimizing microbial necromass accumulation and its contribution to SOC sequestration requires site-specific management.
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Carbono , Suelo , Suelo/química , Estiércol , Nitrógeno , Productos Agrícolas , AgriculturaRESUMEN
Climate change leads to increasing temperature and more extreme hot and drought events. Ecosystem capability to cope with climate warming depends on vegetation's adjusting pace with temperature change. How environmental stresses impair such a vegetation pace has not been carefully investigated. Here we show that dryness substantially dampens vegetation pace in warm regions to adjust the optimal temperature of gross primary production (GPP) ( T opt GPP ) in response to change in temperature over space and time. T opt GPP spatially converges to an increase of 1.01°C (95% CI: 0.97, 1.05) per 1°C increase in the yearly maximum temperature (Tmax ) across humid or cold sites worldwide (37o S-79o N) but only 0.59°C (95% CI: 0.46, 0.74) per 1°C increase in Tmax across dry and warm sites. T opt GPP temporally changes by 0.81°C (95% CI: 0.75, 0.87) per 1°C interannual variation in Tmax at humid or cold sites and 0.42°C (95% CI: 0.17, 0.66) at dry and warm sites. Regardless of the water limitation, the maximum GPP (GPPmax ) similarly increases by 0.23 g C m-2 day-1 per 1°C increase in T opt GPP in either humid or dry areas. Our results indicate that the future climate warming likely stimulates vegetation productivity more substantially in humid than water-limited regions.
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Cambio Climático , Plantas , Estrés Fisiológico , Temperatura , Sequías , EcosistemaRESUMEN
INTRODUCTION: Dysregulated ARID1A expression is frequently detected in lung adenocarcinoma (LUAD) and mediates significant changes in cancer behaviors and a poor prognosis. ARID1A deficiency in LUAD enhances proliferation and metastasis, which could be induced by activation of the Akt signaling pathway. However, no further exploration of the mechanisms has been performed. METHODS: Lentivirus was used for the establishment of the ARID1A knockdown (ARID1A-KD) cell line. MTS and migration/invasion assays were used to examine changes in cell behaviors. RNA-seq and proteomics methods were applied. ARID1A expression in tissue samples was determined by IHC. R software was used to construct a nomogram. RESULTS: ARID1A KD significantly promoted the cell cycle and accelerated cell division. In addition, ARID1A KD increased the phosphorylation level of a series of oncogenic proteins, such as EGFR, ErbB2 and RAF1, activated the corresponding pathways and resulted in disease progression. In addition, the bypass activation of the ErbB pathway, the activation of the VEGF pathway and the expression level changes in epithelial-mesenchymal transformation biomarkers induced by ARID1A KD contributed to the insensitivity to EGFR-TKIs. The relationship between ARID1A and the sensitivity to EGFR-TKIs was also determined using tissue samples from LUAD patients. CONCLUSION: Loss of ARID1A expression influences the cell cycle, accelerates cell division, and promotes metastasis. EGFR-mutant LUAD patients with low ARID1A expression had poor overall survival. In addition, low ARID1A expression was associated with a poor prognosis in EGFR-mutant LUAD patients who received first-generation EGFR-TKI treatment. Video abstract.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Multiómica , Proliferación Celular , Receptores ErbB , Proteínas de Unión al ADN , Factores de TranscripciónRESUMEN
We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.
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Bencenoacetamidas/farmacología , Compuestos de Bencidrilo/farmacología , Digoxina/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Redes Reguladoras de Genes/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Subgrupos de Linfocitos T/efectos de los fármacos , Células Th17/efectos de los fármacos , Androstenoles/química , Animales , Bencenoacetamidas/química , Compuestos de Bencidrilo/química , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Linaje de la Célula/efectos de los fármacos , Citocinas/metabolismo , Digoxina/química , Encefalomielitis Autoinmune Experimental/inmunología , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esclerosis Múltiple/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Fragmentos de Péptidos/inmunología , Unión Proteica/efectos de los fármacos , Relación Estructura-Actividad , Biología de Sistemas , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacosRESUMEN
Lollingite (FeAs2) is considered an arsenic-bearing mineral that is oxidized faster than arsenopyrite. The geometric configuration, chemical valence bond, and microscopic reaction of the oxidation on the surface of lollingite were systematically studied, which are of great significance for understanding the mechanism of oxidative dissolution. X-ray photoelectron spectroscopy (XPS) measurements and density functional theory (DFT) calculations were carried out to characterize the (101) surface oxidation process of lollingite under the O2/O2 + H2O conditions. XPS results confirmed that the participation of water molecules can promote the formation of abundant OH structures on the surface of lollingite, while the relative concentration of O, As(III), and Fe(III) increased. Moreover, the DFT results demonstrated that the (101) As-terminal plane of FeAs2 was the most stable surface with the lowest surface energy. H2O molecules were physically adsorbed onto the Fe atoms of the lollingite surface, while oxygen molecules can readily be adsorbed on the Fe-As2 site by chemical adsorption processes. The oxidation process of the lollingite surface with water includes the following mechanisms: adsorption, dissociation, formation of the hydrogen bond, and desorption. The dissociation of the H2O molecule into OH and H led to the hydroxylation of both Fe and As atoms and the formation of hydrogen bonding. The participation of H2O molecules can also reduce the reaction energy barrier and accelerate the oxidation reaction of the lollingite surface, especially as far as the water dissociation and formation of hydrogen bonds are concerned. According to PDOS data, there is considerable hybridization between the d orbitals of bonded Fe atoms and the p orbitals of O atoms, as well as between the p orbitals of bonded As atoms and the p orbitals of O atoms. Due to a strong propensity for orbital hybridization and bonding between the s orbitals of the H atoms in H2O molecules and the p orbitals of the O atoms on the (101) surface, water molecules have the ability to speed up the oxidation on the surface.