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OBJECTIVE: To explore the impact of the apolipoprotein E (APOE) E4 allele in the gender-specific aging process in glaucoma by illustrating the interaction between risk factors, including the APOE E4 allele, gender and intraocular pressure (IOP), for age at diagnosis (AAD) of glaucoma. DESIGN: A cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis. Data were analyzed in December 2023. PARTICIPANTS: 2,236 glaucoma patients and 103,232 controls. METHODS: We evaluated multivariable-adjusted associations of AAD of glaucoma, APOE E4 allele (0: absence; 1: presence), and IOP using linear mixed model (LMM) analyses across groups stratified by AAD of mean age of menopause (50 years) and gender. MAIN OUTCOMES MEASURES: AAD of glaucoma, APOE E4 allele and IOP. RESULTS: Glaucoma patients were older and had a higher percentage of males and a higher mean IOP compared to controls (all P < 0.001). Further stratifying the glaucoma patients by AAD of 50 and gender, lower IOP (Model 1 adjusted by age, ßIOP=-0.096±0.041, P=0.019) and positive APOE E4 allele (Model 2 adjusted by age and IOP, ße4=1.093±0.488, P=0.026) were associated with an older AAD in females with an AAD < 50 years under univariate LMM. In multivariate LMM adjusted by age (Model 3), the effect size of both factors increased in the multivariate model as the beta-value increased. (ßIOP=-0.111±0.040, P=0.007; ße4=1.235±0.485, P=0.012) (Model 1 vs Model 3: P=0.011). In females with an AAD ≥50 years, only positive APOE E4 allele (adjusted by age and IOP, ße4=-1.121±0.412, P=0.007) was associated with a younger AAD. In males, only higher IOP was associated with an older AAD in those with an AAD ≥50 years (ßIOP=0.088±0.032, P=0.006). CONCLUSIONS: APOE E4 allele may initially delay and later accelerate the development of glaucoma in females around the transition period of 50 years, which is the mean age of menopause, and importantly, this is independent of IOP. Understanding the specific transition states and modifiable factors within each age phase is crucial for developing interventions or strategies that promote healthy aging.
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The cutting technique is extensively used in tea breeding, with key emphasis on promoting the growth of adventitious roots (ARs). Despite its importance in tea cultivation, the mechanisms underlying AR development in tea remain unclear. In this study, we demonstrated the essential role of auxins in the initiation and progression of AR and established that the application of exogenous 1-naphthaleneacetic acid-enhanced AR formation in tissue-cultured seedlings and cuttings. Then, we found that the auxin-responsive transcription factor CsSPL9 acted as a negative regulator of AR development by reducing the levels of free indole-3-acetic acid (IAA) in tea plants. Furthermore, we identified CsGH3.4 as a downstream target of CsSPL9, which was activated by direct binding to its promoter. CsGH3.4 also inhibited AR development and maintained low levels of free IAA. Thus, these results revealed the inhibitory effect of the auxin-responsive CsSPL9-CsGH3.4 module on AR development by reducing free IAA levels in tea. These findings have significant theoretical and practical value for enhancing tea breeding practices.
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Camellia sinensis , Regulación de la Expresión Génica de las Plantas , Ácidos Indolacéticos , Proteínas de Plantas , Raíces de Plantas , Factores de Transcripción , Ácidos Indolacéticos/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Raíces de Plantas/genética , Camellia sinensis/crecimiento & desarrollo , Camellia sinensis/genética , Camellia sinensis/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Reguladores del Crecimiento de las Plantas/metabolismo , Ácidos Naftalenoacéticos/farmacología , Plantones/crecimiento & desarrollo , Plantones/genética , Plantones/metabolismo , Regiones Promotoras GenéticasRESUMEN
Laser-based light detection and ranging (LIDAR) offers a powerful tool to real-timely map spatial information with exceptional accuracy and owns various applications ranging from industrial manufacturing, and remote sensing, to airborne and in-vehicle missions. Over the past two decades, the rapid advancements of optical frequency combs have ushered in a new era for LIDAR, promoting measurement precision to quantum noise limited level. For comb LIDAR systems, to further improve the comprehensive performances and reconcile inherent conflicts between speed, accuracy, and ambiguity range, innovative demodulation strategies become crucial. Here we report a dispersive Fourier transform (DFT) based LIDAR method utilizing phase-locked Vernier dual soliton laser combs. We demonstrate that after in-line pulse stretching, the delay of the flying pulses can be identified via the DFT-based spectral interferometry instead of temporal interferometry or pulse reconstruction. This enables absolute distance measurements with precision starting from 262 nm in single shot, to 2.8 nm after averaging 1.5 ms, in a non-ambiguity range over 1.7 km. Furthermore, our DFT-based LIDAR method distinctly demonstrates an ability to completely eliminate dead zones. Such an integration of frequency-resolved ultrafast analysis and dual-comb ranging technology may pave a way for the design of future LIDAR systems.
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BACKGROUND: Postweaning is a pivotal period for brain development and individual growth. As an important chemical used in medicines, foods and beverages, sodium citrate (SC) is commonly available. Although some effects of SC exposure on individual physiology have been demonstrated, the potential long-lasting effects of postweaning dietary SC exposure on social behaviours are still elusive. METHODS: Both postweaning male and female C57BL/6 mice were exposed to SC through drinking water for a total of 3 weeks. A series of behavioural tests, including social dominance test (SDT), social interaction test (SIT), bedding preference test (BPT) and sexual preference test (SPT), were performed in adolescence and adulthood. After these tests, serum oxytocin (OT) levels and gut microbiota were detected. RESULTS: The behavioural results revealed that postweaning SC exposure decreased the social dominance of male mice in adulthood and female mice in both adolescence and adulthood. SC exposure also reduced the sexual preference rates of both males and females, while it had no effect on social interaction behaviour. ELISA results indicated that SC exposure decreased the serum OT levels of females but not males. 16S rRNA sequencing analysis revealed a significant difference in ß-diversity after SC exposure in both males and females. The correlation coefficient indicated the correlation between social behaviours, OT levels and dominant genera of gut microbiota. CONCLUSION: Our findings suggest that postweaning SC exposure may have enduring and sex-dependent effects on social behaviours, which may be correlated with altered serum OT levels and gut microbiota composition.
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Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Oxitocina , Conducta Social , Citrato de Sodio , Animales , Masculino , Femenino , Ratones , Oxitocina/sangre , Microbioma Gastrointestinal/efectos de los fármacos , Citrato de Sodio/farmacología , Destete , Conducta Animal/efectos de los fármacos , Predominio Social , Caracteres Sexuales , Factores SexualesRESUMEN
Synergetic management of waste activated sludge, heavy metals (HMs) and CO2 for their valorization and cyclic utilization is rarely reported. Herein, we employed sludge-derived extracellular polymeric substances (EPS) and HMs in wastewater to fabricate a gas diffusion electrode (GDE) for electrochemical CO2 reduction. This approach atomically dispersed Ni at each nanofiber of the GDE. Abundant N element in the EPS proved to play a key role in the formation of Nx-Ni (mixture of N3-Ni and N4-Ni) sites for highly efficient CO2 to CO conversion. The atomical Ni3+ shows high catalytic activity. Direct gaseous CO2 reduction in a membrane electrode assembly generated a current density up to 50 mA·cm-2 with CO:H2 ratio of â¼100 and â¼75% FECO under 2.69 cell voltage. This strategy takes advantage of all waste streams generated on site and consolidates traditionally separated treatment processes to save costs, produces value-added products and generates carbon benefits during wastewater treatment.
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Moderate cold stimulation regulates the thymus's growth and function and facilitates cold acclimatization in broilers. However, the underlying mechanism remains unknown. To explore the possible mechanism of the thymus in cold-acclimated broilers against cold stress, 240 one-day-old Arbor Acres (AA) broilers were assigned to 2 groups randomly. The control group (C) was housed at conventional temperatures. The temperature during the first week was 33°C to 34°C. Between the ages of 8 and 32 d, the temperature was lowered by 1°C every 2 d, i.e., gradually from 32°C to 20°C, and then maintained at 20°C until 42 d of age. The cold-acclimated group (C-3) was housed at the same temperature as C from 1 to 7 d after birth. Between 8 and 42 d, the temperature of C-3 was 3°C colder than C. After 24 h exposure to acute cold stress (ACS) at 42 d, C and C-3 were named as S and S-3. The results showed that ACS was able to induce oxidation stress, modulate PI3K/AKT signal, and cause necroptosis and apoptosis in broiler thymus. By contrast, cold acclimation could alleviate apoptosis and necroptosis induced by cold stress via alleviating oxidative stress, efficiently activating the PI3K/AKT signal, as well as decreasing apoptotic and necrotic genes' levels. This study offers a novel theoretical basis for cold acclimation to improve the body's cold tolerance.
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Aclimatación , Apoptosis , Pollos , Frío , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Timo , Animales , Pollos/fisiología , Timo/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Necroptosis/fisiología , Transducción de Señal , Proteínas Aviares/metabolismo , Proteínas Aviares/genética , Distribución Aleatoria , Respuesta al Choque por Frío , MasculinoRESUMEN
Global warming is increasing the frequency and intensity of heat waves and droughts. One important phase in the life cycle of plants is seed germination. To date, the association of the temperature and water potential thresholds of germination with seed traits has not been explored in much detail. Therefore, we set up different temperature gradients (5-35 °C), water potential gradients (-1.2-0 MPa), and temperature × water potential combinations for nine native plants in the Loess Plateau region to clarify the temperature and water combinations suitable for their germination. Meanwhile, we elucidated the temperature and water potential thresholds of the plants and their correlations with the mean seed mass and flatness index by using the thermal time and hydrotime models. According to our findings, the germination rate was positively correlated with the germination percentage and water potential, with the former rising and the latter decreasing as the temperature increased. Using the thermal time and hydrotime models, the seed germination thresholds could be predicted accurately, and the germination thresholds of the studied species varied with an increase in germination percentage. Moreover, temperature altered the impact of water potential on the germination rate. Overall, the base water potential for germination, but not the temperature threshold, was negatively correlated with mean seed mass and was lower for rounder seeds than for longer seeds. This study contributes to improving our understanding of the seed germination characteristics of typical plants and has important implications for the management and vegetation restoration of degraded grasslands.
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Aggression is an instinctive behavior that has been reported to be influenced by early-life stress. However, the potential effects of acute stress during the postweaning period, a key stage for brain development, on defensive aggression and the associated mechanism remain poorly understood. In the present study, aggressive behaviors were evaluated in adolescent mice exposed to postweaning stress. Serum corticosterone and testosterone levels, neural dendritic spine density, and gut microbiota composition were determined to identify the underlying mechanism. Behavioral analysis showed that postweaning stress reduced locomotor activity in mice and decreased defensive aggression in male mice. ELISA results showed that postweaning stress reduced serum testosterone levels in female mice. Golgi staining analysis demonstrated that postweaning stress decreased neural dendritic spine density in the medial prefrontal cortex of male mice. 16S rRNA sequencing results indicated that postweaning stress altered the composition of the gut microbiota in male mice. Combined, these results suggested that postweaning stress alters defensive aggression in male mice, which may be due to changes in neuronal structure as well as gut microbiota composition. Our findings highlight the long-lasting and sex-dependent effects of early-life experience on behaviors.
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Microbioma Gastrointestinal , Ratones , Animales , Masculino , Femenino , Microbioma Gastrointestinal/fisiología , ARN Ribosómico 16S/genética , Encéfalo , Conducta Animal , TestosteronaRESUMEN
BACKGROUND AND AIMS: Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, previous studies only focused on baseline frailty status, not taking into consideration the changes in frailty status during follow-up. The aim of this study was to investigate the associations of changes in frailty status with incident CVD. METHODS: This study used data of three prospective cohorts: China Health and Retirement Longitudinal Study (CHARLS), English Longitudinal Study of Ageing (ELSA), and Health and Retirement Study (HRS). Frailty status was evaluated by the Rockwood frailty index and classified as robust, pre-frail, or frail. Changes in frailty status were assessed by frailty status at baseline and the second survey which was two years after the baseline. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease (including angina, heart attack, congestive heart failure, and other heart problems) or stroke. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) after adjusting for potential confounders. RESULTS: A total of 7116 participants from CHARLS (female: 48.6%, mean age: 57.4 years), 5303 from ELSA (female: 57.7%, mean age: 63.7 years), and 7266 from HRS (female: 64.9%, mean age: 65.1 years) were included according to inclusion and exclusion criteria. The median follow-up periods were 5.0 years in the CHARLS, 10.7 years in the ELSA, and 9.5 years in the HRS. Compared with stable robust participants, robust participants who progressed to pre-frail or frail status had increased risks of incident CVD (CHARLS, HR = 1.84, 95% CI: 1.54-2.21; ELSA, HR = 1.53, 95% CI: 1.25-1.86; HRS, HR = 1.59, 95% CI: 1.31-1.92). In contrast, frail participants who recovered to robust or pre-frail status presented decreased risks of incident CVD (CHARLS, HR = 0.62, 95% CI: 0.47-0.81; ELSA, HR = 0.49, 95% CI: 0.34-0.69; HRS, HR = 0.70, 95% CI: 0.55-0.89) when compared with stable frail participants. These decreased risks of incident CVD were also observed in pre-frail participants who recovered to robust status (CHARLS, HR = 0.66, 95% CI: 0.52-0.83; ELSA, HR = 0.65, 95% CI: 0.49-0.85; HRS, HR = 0.71, 95% CI: 0.56-0.91) when compared with stable pre-frail participants. CONCLUSIONS: Different changes in frailty status are associated with different risks of incident CVD. Progression of frailty status increases incident CVD risks, while recovery of frailty status decreases incident CVD risks.
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Enfermedades Cardiovasculares , Fragilidad , Humanos , Femenino , Anciano , Persona de Mediana Edad , Fragilidad/epidemiología , Enfermedades Cardiovasculares/epidemiología , Estudios Longitudinales , Estudios Prospectivos , Anciano FrágilRESUMEN
Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein-protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR.
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Neuropatías Amiloides Familiares , Prealbúmina , Humanos , Prealbúmina/genética , Prealbúmina/metabolismo , Prealbúmina/uso terapéutico , Reposicionamiento de Medicamentos , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/diagnóstico , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Obesity induces insulin resistance and chronic inflammation, impacting human health. The relationship between obesity, gut microbiota, and regulatory mechanisms has been studied extensively. Dendrobium officinale polysaccharide (DOP), a traditional Chinese herbal medicine, potentially reduces insulin resistance. However, the mechanism through which DOP affects gut microbiota and alleviates obesity-induced insulin resistance in rats requires further investigation. RESULTS: The current study aimed to assess the impact of DOP on gut microbiota and insulin resistance in rats on a high-fat diet. The results revealed that DOP effectively reduced blood lipids, glucose disorders, oxidative stress, and inflammatory infiltration in the liver of obese Sprague Dawley rats. This was achieved by downregulating SOCS3 expression and upregulating insulin receptor substrate-1 (IRS-1) by regulating the JAK/STAT/SOCS3 signaling pathway. Notably, DOP intervention enhanced the abundance of beneficial gut microbiota and reduced harmful microbiota. Correlation analysis demonstrated significant associations among intestinal microbiota, SOCS3-mediated IRS-1 expression, and inflammatory factors. CONCLUSION: Dendrobium officinale polysaccharide regulated the gut microbiota, enhanced IRS-1 expression, and mitigated liver injury and insulin resistance due to a high-fat diet. These findings depict the potential anti-insulin resistance properties of DOP and offer further evidence for addressing obesity and its complications. © 2023 Society of Chemical Industry.
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Dendrobium , Microbioma Gastrointestinal , Resistencia a la Insulina , Ratas , Humanos , Animales , Dendrobium/química , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Ratas Sprague-Dawley , Polisacáridos/química , Transducción de Señal , Obesidad/tratamiento farmacológico , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismoRESUMEN
BACKGROUND: With the widespread adoption of smartphones, there has been a notable increase in problematic mobile phone use (PMPU), particularly prevalent among college students. Research suggests that apart from being associated with various problematic behaviors, this excessive mobile phone use might also have an impact on individual personality traits, such as time management disposition (TMD), which plays a significant role in individual motivation and psychological well-being. While previous literature has identified a negative relationship between PMPU and TMD, few studies have delved into the underlying mediating mechanism. Thus, the main aim of this study was to examine the chain mediating effect of sleep quality and cognitive flexibility on the relationship between PMPU and TMD. METHODS: A total of 921 Chinese college students completed the questionnaire. We collected basic information about the participants and assessed their PMPU, TMD, sleep quality, and cognitive flexibility using the Problematic Mobile Phone Use Scale-10, Adolescence Time Management Disposition Inventory, Pittsburgh Sleep Quality Index scale and Cognitive Flexibility Inventory. RESULTS: The results indicated a significant correlation among all the variables. Moreover, we noted that both sleep quality and cognitive flexibility fully mediated the association between PMPU and TMD. Additionally, a chain mediating effect involving sleep quality and flexibility in this relationship was also identified. CONCLUSION: We found that sleep quality and cognitive flexibility had a series of multiple mediating effects in the pathway from PMPU to TMD, and both significantly mediated TMD. These findings indicated that impaired cognitive function and sleep quality may contribute to time management difficulties resulting from PMPU, suggesting that problematic behaviors like PMPU can impact one's personality traits. Therefore, interventions should be enhanced to mitigate the adverse effects of PMPU.
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Uso del Teléfono Celular , Adolescente , Humanos , Calidad del Sueño , Administración del Tiempo , Estudiantes/psicología , Motivación , CogniciónRESUMEN
Cableways have been widely used in industrial areas, cities, and scenic spots due to their advantages, such as being a convenient mode of transportation, time-saving, labor-saving, and low cost, as well as offering environmental protection. To ensure the safe operation of a cableway, based on the characteristic that the velocity of the cableway bracket is approximately zero in a static deformation monitoring environment, a deformation monitoring method called zero velocity update (ZUPT)-based GNSS/IMU tightly coupled algorithm with the constraint of the Earth's rotation angular velocity was proposed. The proposed method can effectively solve the problem of a single GNSS being unable to output attitude, which is directly related to the status of wire ropes and cable cars. Meanwhile, ZUPT is used to restrain the Kalman filter's divergence when IMU is stationary. However, the improvements of ZUPT on attitude are not obvious, so the constraint of the Earth's rotation angular velocity was applied. The performance of the proposed method was evaluated through monitoring the cableway bracket of the Yimeng Mountain Tourism area in Shandong. Compared with the ZUPT-based GNSS/IMU tightly coupled algorithm (ZUPT-TC), the proposed method can further constrain the error accumulation of IMU while stationary and, therefore, it can provide reliable position and attitude information on cableway brackets.
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BACKGROUND: Whether and to what extent serum uric acid (SUA) mediates the association between combined lifestyle behaviors and type 2 diabetes mellitus (T2DM) remain unclear. This study aimed to investigate the role of SUA in the relationship between healthy lifestyle scores (HLS) and the incidence of T2DM. METHODS: This prospective study used data from Zhejiang Metabolic Syndrome cohort. A HLS (5-point scale including healthy waist circumference (WC), never smoking, high physical activity, healthy diet and moderate alcohol intake) was estimated in 13,919 participants, who had SUA at baseline examination in 2009-2014, and were followed-up to 2021-2022 to ascertain incident of T2DM. Cox proportional hazards models and mediation analysis were used to examine the associations between HLS, SUA and T2DM. RESULTS: We included 13,919 participants aged 18 years or older without diabetes at baseline (mean age 54.6 [SD 13.9] years, 58.7% female). During a median follow-up of 9.94 years, 645 cases of T2DM occurred. Compared with participants with a poor HLS, those with 4-5 low-risk lifestyle factors showed a 60% reduction in the risk of developing T2DM (adjusted HR, 0.40; 95% CI: 0.28-0.57). Further, the population-attributable risk percent (95% CI) of T2DM for poor adherence to the overall healthy lifestyle (< 4 low-risk factors) was 43.24% (30.02%, 56.46%). The HLS was inversely associated with SUA level. With per score increased in HLS, the beta (95% CI) of SUA (log transformed) was - 0.03 (- 0.03, - 0.02), and the odds ratio (95% CI) of hyperuricemia was 0.82 (0.77, 0.86). The relationship between the HLS and risk of T2DM was mediated by SUA with a 13.06% mediation effect. There was no significant combined effect of HLS and SUA on risk of T2DM (P = 0.097). CONCLUSIONS: The relationship between overall healthy lifestyle behaviors and T2DM was reconfirmed and the association appeared to be mediated by SUA. The mediation effect of baseline SUA was more pronounced among women who were below 60 years old.
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Mountain treelines are thought to be sensitive to climate change. However, how climate impacts mountain treelines is not yet fully understood as treelines may also be affected by other human activities. Here, we focus on "closed-loop" mountain treelines (CLMT) that completely encircle a mountain and are less likely to have been influenced by human land-use change. We detect a total length of ~916,425 km of CLMT across 243 mountain ranges globally and reveal a bimodal latitudinal distribution of treeline elevations with higher treeline elevations occurring at greater distances from the coast. Spatially, we find that temperature is the main climatic driver of treeline elevation in boreal and tropical regions, whereas precipitation drives CLMT position in temperate zones. Temporally, we show that 70% of CLMT have moved upward, with a mean shift rate of 1.2 m/year over the first decade of the 21st century. CLMT are shifting fastest in the tropics (mean of 3.1 m/year), but with greater variability. Our work provides a new mountain treeline database that isolates climate impacts from other anthropogenic pressures, and has important implications for biodiversity, natural resources, and ecosystem adaptation in a changing climate.
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Ecosistema , Árboles , Humanos , Temperatura , Cambio Climático , BiodiversidadRESUMEN
Primary liver hepatocellular carcinoma (HCC) is the third most deadly malignancy worldwide,in part, because it is often diagnosed at an advanced stage. Thus, molecular markers are needed to aid in the early diagnosis and treatment of HCC. Expression of abnormal mesoderm posterior-1 (MESP1) promotes tumorigenesis; however,its role in the regulation of HCC proliferation, apoptosis,and invasion is unknown. Here,we analyzed data in The Cancer Genome Atlas (TCGA)and Genotype Tissue Expression (GTEx) databases on the pan-cancer expression of MESP1 and its relationship with clinical characteristics and prognosis of patients with HCC. The expression of MESP1 was measured in 48 HCC tissues using immunohistochemical staining,and the results were correlated with clinical stage, tumor differentiation, tumor size,and metastasis. MESP1 expression was downregulated using small interfering RNA (siRNA) in the HCC cell lines HepG2 and Hep3B,and cell viability, proliferation,cell cycle, apoptosis,and invasion were analyzed. Finally,we also evaluated the tumor suppression effect of MESP1 downregulation combined with 5-fluorouracil (5-FU) treatment. Our results showed that MESP1 is a pan-oncogene associated with poor prognosis in patients with HCC. siRNA-induced downregulation of MESP1 expression in HepG2 and Hep3B cells exhibited downregulation of ß-catenin and GSK3ß expression 48h after transfection, along with an increase in apoptosis rate, arrest in the G1-S phase,and a decrease in mitochondrial membrane potential. Moreover,the expression levels of c-Myc, PARP1, bcl2, Snail1, MMP9, and immune checkpoint genes (TIGIT, CTLA4,LAG3,CD274,and PDCD1) were downregulated, while those of caspase3 and E-cadherin were upregulated. Tumor cells also showed decreased migration ability. Furthermore, siRNA interference of MESP1 expression combined with 5-FU-treatment of HCC cells significantly enhanced the G1-S phase block and apoptosis. MESP1 showed an aberrant high expression in HCC and was associated with poor clinical outcomes; therefore, MESP1 may be a potential target for the diagnosis and treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fluorouracilo/farmacología , Transición Epitelial-Mesenquimal/genética , Línea Celular Tumoral , ARN Interferente Pequeño/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
OBJECTIVES: Hereditary transthyretin amyloidosis (ATTRv) is a rare, fatal, autosomal dominant disease with more than 140 mutations discovered. Three phenotypes of amyloid infiltration are neuropathy (ATTRv-PN), cardiopathy (ATTRv-CM), and neuropathy + cardiopathy (ATTRv-MIX). The lack of ATTR-specific biomarkers, difficulties in biopsy evidence, and limited known pathogenic mechanisms have made diagnosis difficult. Newly emerging noninvasive measures for monitoring progression and disease-modifying therapies have improved early diagnosis and patient management. METHODS: Our research applies the latest technology, Data-Independent Acquisition-Based Quantitative Proteomics (DIA), to reveal comprehensive plasma protein profiles in the natural history of Chinese patients with hereditary transthyretin amyloidosis (ATTRv). We analyzed differentially expressed proteins (DEPs) in three phenotypes (ATTRv-PN, ATTRv-CM, and ATTRv-MIX). RESULTS: Serum samples were collected from a total of 18 patients (6 ATTRv-PN, 5 ATTRv-CM, and 7 ATTRv-MIX patients) and 20 healthy participants as a control group. Combined with the results of the proteomic and bioinformatic analyses, we found 30 DEPs and protein interaction networks clustered in KRT family proteins and DSC3 between ATTRv-PN and the control, which were rich in the estrogen signaling pathway and the cell adhesion molecule (CAM) pathway. CONCLUSION: This study demonstrates a global and significant proteomic profile in different stages of ATTRv.
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Neuropatías Amiloides Familiares , Proteínas Sanguíneas , Humanos , Neuropatías Amiloides Familiares/sangre , Proteínas Sanguíneas/análisis , ProteómicaRESUMEN
The lactation period is an important period for individual development and a sensitive period for the behavioral phenotypes and plasticity of individual offspring. Early life experiences (e.g., maternal deprivation (MD) and neglect) have significant long-lasting and dual effects on individual stress reactivities during adulthood. Theoretically, stress inoculation can improve the adaptive capacity of the body, but overstress can lead to dysfunction when adaptive mechanisms fail.To date, the potential effects of late lactational MD on the socioemotional behaviors of mouse offspring during adulthood are still not fully understood. In the present study, mice were subjected to early deprivation by individually separating pups from their dam for 0 min, 15 min, and 3 h per day from PND 13-25. The social dominance test (SDT), social interaction test (SI), open field test (OFT), and forced swim test (FST) were carried out during adulthood. The results showed that the social dominance of male mice in the 15 min/d MD group significantly increased, especially in low-rank mice. In the 3 h/d MD group, the social dominance of female mice was decreased, especially in the lower-rank mice. The anxiolytic and antidepressant-like effects of the 15 min/d MD group were significantly increased in male mice. Our study provides direct evidence that MD during late lactation period results in long-lasting effects on social dominance as well as on anxiety and depression phenotypes in a sex-dependent manner.
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Ansiedad , Privación Materna , Animales , Ratones , Masculino , Femenino , Ansiedad/psicología , Conducta Animal , Natación/psicología , Lactancia , Estrés PsicológicoRESUMEN
Hepatocellular carcinoma (HCC) is an aggressive tumor triggered by various factors such as virus infection and alcohol abuse. Glucuronomannan polysaccharide (Gx) is a subtype of fucoidans that possesses many bioactivities, but its anti-tumor activities in HCC have not been reported. In this paper, the anti-tumor effects of glucuronomannan oligosaccharides (Gx) and its sulfated derivatives (GxSy) on hepatocarcinoma Huh7.5 cells were investigated. The anti-proliferation, anti-metastasis activities, and underlying mechanism of Gx and GxSy on Huh7.5 cells were analyzed and compared by MTT, wound healing, transwell, and western blotting assays, respectively. Results showed that the best anti-proliferation effects were G4S1 and G4S2 among 13 drugs, which were 38.67% and 30.14%, respectively. The cell migration rates were significantly inhibited by G2S1, G4S2, G6S2, and unsulfated Gn. In addition, cell invasion effects treated with G4S1, G4S2, and G6S1 decreased to 48.62%, 36.26%, and 42.86%, respectively. Furthermore, sulfated G4 regulated the expression of (p-) FAK and MAPK pathway, and sulfated G6 down-regulated the MAPK signaling pathway while activating the PI3K/AKT pathway. On the contrary, sulfated G2 and unsulfated Gx had no inhibited effects on the FAK-mTOR pathway. These results indicated that sulfated Gx derivatives have better anti-tumor activities than unsulfated Gx in cell proliferation and metastasis process in vitro, and those properties depend on the sulfation group levels. Moreover, degrees of polymerization of Gx also played a vital role in mechanisms and bioactivities. This finding shows the structure-activity relationship for developing and applying the marine oligosaccharide candidates.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Sulfatos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Oligosacáridos/farmacología , Proliferación Celular , Movimiento Celular , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: Human cytomegalovirus (HCMV), a member of the ß-herpesvirus family, causes the establishment of a latent infection that persists throughout the life of the host and can be reactivated when immunity is weakened. To date, there is no vaccine to prevent HCMV infection, and clinically approved drugs target the stage of viral replication and have obvious adverse reactions. Thus, development of novel therapeutics is urgently needed. METHODS: In the current study, we identified a naturally occurring pterostilbene that inhibits HCMV Towne strain replication in human diploid fibroblast WI-38 cells through Western blotting, qPCR, indirect immunofluorescence assay, tissue culture infective dose assays. The time-of-addition experiment was carried out to identify the stage at which pterostilbene acted. Finally, the changes of cellular senescence biomarkers and reactive oxygen species production brought by pterostilbene supplementation were used to partly elucidate the mechanism of anti-HCMV activity. RESULTS: Our findings revealed that pterostilbene prevented lytic cytopathic changes, inhibited the expression of viral proteins, suppressed the replication of HCMV DNA, and significantly reduced the viral titre in WI-38 cells. Furthermore, our data showed that pterostilbene predominantly acted after virus cell entry and membrane fusion. The half-maximal inhibitory concentration was determined to be 1.315 µM and the selectivity index of pterostilbene was calculated as 26.73. Moreover, cell senescence induced by HCMV infection was suppressed by pterostilbene supplementation, as shown by a decline in senescence-associated ß-galactosidase activity, decreased production of reactive oxygen species and reduced expression of p16, p21 and p53, which are considered biomarkers of cellular senescence. CONCLUSION: Together, our findings identify pterostilbene as a novel anti-HCMV agent that may prove useful in the treatment of HCMV replication.