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In the past decade, the outbreak of Streptococcus agalactiae has caused significant economic losses in tilapia farming. Vaccine immunization methods and strategies have gradually evolved from single-mode to multi-mode overall prevention and control strategies. In this study, an inactivated vaccine of S. agalactiae with a chitosan oligosaccharide (COS) adjuvant was constructed using different administration methods: intraperitoneal injection (Ip), immersion combined with intraperitoneal injection (Im + Ip), immersion combined with oral administration (Im + Or), and oral administration (Or). Safety analysis revealed no adverse effects on tilapia, and the vaccine significantly promoted fish growth and development when administered through Im + Or or Or immunization. Following vaccination, innate immunity parameters including SOD, ACP and CAT activities were all significantly enhanced. Additionally, specific serum IgM antibodies reached their highest level at the 6th week post vaccination. Skin and intestinal mucus IgT antibodies reached peaked at the 6th and 7th week post vaccination, respectively. The relative peak expression values for IL-8, IL-12, MHC-I, MHC-II, IgM, IgT, CD4, CD8, TNFα, IFNγ from Im + Ip group were significantly higher than those in Ip group, Im + Or group and Or group in most cases (p < 0.05). Importantly, the relative protection survival of Im + Ip group was the highest (78.6%), followed by the Ip group (71.4%), the Or group (64.3%) and the Im + Or group (57.1%). In summary, this study encourages further research on multi-channel immunization strategies of other kinds of vaccines in other aquatic economic animals to improve their disease resistance.
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Quitosano , Cíclidos , Enfermedades de los Peces , Infecciones Estreptocócicas , Tilapia , Animales , Streptococcus agalactiae , Vacunas Bacterianas , Vacunación , Inmunidad Innata , Inmunoglobulina M , OligosacáridosRESUMEN
The highest theoretical capacity and lowest redox potential of lithium metal make lithium-based batteries the "holy grail" of the next-generation batteries. However, the uncontrollable dendrite growth and infinite volume change of lithium seriously hinder the real-world implementation of lithium-based batteries. Herein, a flexible MXene@iodine-doped red phosphorus (MXene@RP) paper with iodine-doped red phosphorous particles evenly distributed on the surface and interlayer of MXene matrix is designed by a simple vapor condensation reduction approach. The MXene@RP paper can be used as an efficient matrix to enable dendrite-free lithium deposition. On the one hand, the iodine doping alleviates the low conductivity shortcoming of red phosphorus, making it facilitate homogeneous lithium nucleation, thus promoting uniform lithium deposition and suppressing dendrite growth. On the other hand, the unique layered structure of conductive MXene paper provides ion transport channels and free spaces for lithium loading, alleviating the volume change induced structural damage. As a result, the MXene@RP paper with preloaded lithium exhibits long-term cycling stability. Particularly, a full cell based on Li-MXene@RP anode can maintain 81.4% of the initial capacity after 600 cycles at 4 C. The MXene@RP-based anode increases the potential applications of MXene and provides a guide for the design of dendrite-free lithium hosts.
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Evidence on the associations of prolonged ambient pollutants exposure with chronic non-communicable diseases among middle-aged and elderly residents is still limited. This prospective cohort study intends to investigate the long-term effects of ambient pollution on hypertension and diabetes incidence among relatively older residents in China. Individual particulate matter exposure levels were estimated by satellite-based model. Individual gaseous pollutants exposure levels were estimated by Inverse Distance Weighted model. A Cox regression model was employed to assess the risks of hypertension and diabetes morbidity linked to air pollutants exposures. The cross-product term of ambient pollutants exposure and covariates was further added into the regression model to test whether covariates would modify these air pollution-morbidity associations. During the period from 2014 to 2018, a total of 97,982 subjects completed follow-up. 12,371 incidents of hypertension and 2034 of diabetes occurred. In the multi-covariates model, the hazard ratios (HR) and 95% confidence interval (CI) were 1.49 (1.45-1.52), 1.28 (1.26-1.30), 1.17 (1.15-1.18), 1.21 (1.17-1.25) and 1.33 (1.31-1.35) for hypertension morbidity per 10 µg/m3 increment in PM1, PM2.5, PM10, NO2 and SO2, respectively. For diabetes onsets, the HR (95% CI) were 1.17 (1.11-1.23), 1.09 (1.04-1.13), 1.06 (1.02-1.09), 1.02 (0.95-1.10), and 1.24 (1.19-1.29), respectively. In addition, for hypertension analyses, the effect estimates were more pronounced in the participants with age <60 years old, BMI ≥24 kg/m2, and frequent alcohol drinking. These findings provided the evidence on elevated risks of morbidity of hypertension and diabetes associated with prolonged ambient pollutants exposure at relatively high levels.
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Contaminantes Atmosféricos , Contaminación del Aire , Hipertensión , Enfermedades no Transmisibles , Anciano , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , China/epidemiología , Estudios de Cohortes , Exposición a Riesgos Ambientales/análisis , Humanos , Hipertensión/inducido químicamente , Hipertensión/epidemiología , Incidencia , Persona de Mediana Edad , Dióxido de Nitrógeno/análisis , Enfermedades no Transmisibles/epidemiología , Material Particulado/análisis , Material Particulado/toxicidad , Estudios ProspectivosRESUMEN
Bone metastasis is one of the common phenomena in the late stage of lung cancer. Inhibition of bone metastasis can improve the survival of lung cancer patients. However, the current drugs for the treatment of bone metastasis have shown little effect on overall survival. Therefore, there is an urgent necessity to identify novel drugs capable of preventing and treating bone metastasis of lung cancer. Our study determined that icaritin (ICT) can inhibit lung cancer-mediated osteoclastogenesis and induce the apoptosis of osteoclasts. Exposure to ICT increased the activation of adenosine 5'-monophosphate-activated protein kinase (AMPK), reduced the activation of mammalian target of rapamycin (mTOR) and decreased the expression of bcl-2. The bioactivity of ICT on osteoclastogenesis was associated with the regulation of the AMPK/mTOR signaling pathway. Blocking AMPK significantly increased osteoclast differentiation, decreased osteoclast apoptosis and canceled the effects of ICT on the phosphorylation of AMPK as well as the inhibition of mTOR and bcl-2. Furthermore, ICT decreased the levels of IL-6 and TNF-α in osteoclasts, while the AMPK inhibitor compound C significantly abolished the inhibitory effects of ICT on IL-6 and TNF-α. Thus, the present study demonstrated that ICT may be a potential natural agent for the treatment of bone metastasis in patients with lung cancer.
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Flavonoides/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Osteogénesis/efectos de los fármacos , Células A549 , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Humanos , Interleucina-6/metabolismo , Neoplasias Pulmonares/metabolismo , Ratones , Osteoclastos/efectos de los fármacos , Osteoclastos/patología , Osteogénesis/fisiología , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To examine the effects of whole-body vibration on neuromuscular performance in people with spinal cord injury and evaluate the safe and effective vibration protocols. METHODS: PubMed, EMBASE, CINAHL and PEDro were mainly searched for English literatures. Other data sources were ClinicalTrials.gov , Current Controlled Trials and reference lists of all relevant articles. The PEDro scale was used to evaluate the methodological quality, and the Oxford Centre for Evidence-based Medicine level of evidence was used to assess the level of evidence. Basic information and whole-body vibration protocols were extracted by two independent researchers. Any disagreements were resolved by the third researcher. RESULTS: Of the eight included studies involving 94 individuals with spinal cord injury and 24 able-bodied participants, six of them reported beneficial effects of whole-body vibration on muscle activation and the other two on muscle spasticity. Based on the reviewed studies, an intermittent mode of whole-body vibration (frequency: 10-50 Hz; amplitude: 0.6-4 mm) is less likely to cause adverse events when applying to spinal cord injury subjects standing on platform (knees flexed at 10°-40°). CONCLUSIONS: The strength of evidence is insufficient in supporting the benefits of whole-body vibration on neuromuscular performance in individuals with spinal cord injury. The intermittent vibration (frequency: 10-50 Hz; amplitude: 0.6-4 mm; knee flexion: 10°-40°) may be the possible effective range and have good compliance.
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Traumatismos de la Médula Espinal/rehabilitación , Vibración/uso terapéutico , Humanos , Espasticidad Muscular/prevención & control , Atrofia Muscular/prevención & controlRESUMEN
OBJECTIVE: To explore the effects of therapeutic ultrasound with sham or no intervention on pain, physical function and safety outcomes in patients with knee osteoarthritis. DATA SOURCES: This systematic review was searched on CENTRAL, EMBASE, MEDLINE, CINAHL, Physiotherapy Evidence Database, Open Gray on 4 September 2015. Trials included randomized controlled trials that compared therapeutic ultrasound with a sham or no intervention in patients with osteoarthritis of the knee. REVIEW METHODS: Eligible trials and extracted data were identified by two independent investigators. Standardized mean differences (SMDs) and 95% confidence interval (CI) were calculated for pain and physical function outcomes. Heterogeneity was assessed by the I2 test and inverse-variance random-effects analysis was applied to all trials. RESULTS: Ten randomized controlled trials (645 patients) met the inclusion criteria. Therapeutic ultrasound showed a positive effect on pain (SMD = -0.93, 95%, CI = -1.22 to -0.64, p < 0.01, p for heterogeneity = 0.12, I2 = 42%). For physical function, therapeutic ultrasound was advantageous for reducingWestern Ontario and McMaster Universities physical function score (SMD = -0.37, 95% CI = -0.73 to -0.01, p = 0.04, p for heterogeneity = 0.94, I2 = 0%). In terms of safety, no occurrence of adverse events caused by therapeutic ultrasound was reported in any trial. CONCLUSION: The authors suggested that therapeutic ultrasound is beneficial for reducing knee pain and improving physical functions in patients with knee osteoarthritis and could be a safe treatment.
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Osteoartritis de la Rodilla/terapia , Terapia por Ultrasonido , Humanos , Recuperación de la Función , Resultado del TratamientoRESUMEN
The introduction of metal Single-atom (SA) to construct lithium-philic active sites shows the ability to guide uniform lithium deposition and improve the stability of lithium hosts. Nevertheless, the development of facile and expedient methods for synthesizing SA remains a considerable challenge. Herein, The SA metal loaded on graphene (Bi@LrGO) is designed by laser-induced solid-phase strategy. The bismuth salts simultaneously decompose under the high local temperature and in the reductive atmosphere induced by laser to form SA metal. Simultaneously, graphene oxide (GO) nanosheets absorb photon energy to be reduced/graphitized into graphene, which serves as anchoring sites for Bismuth Sing-atom (Bi SA) immobilization. The SA metals, supported on the graphene not only provide sufficient lithiophilic sites but also significantly increase the adsorption energy (-2.11 eV) with lithium atoms, promote the uniform nucleation and deposition of lithium, and inhibit the growth of lithium dendrites. Additionally, the layered structure of the graphene film adapts to the volume change during the repeated lithium plating/stripping process. Therefore, the symmetrical battery-based Li deposited on Bi@LrGO (Bi@LrGO@Li) achieves an ultra-long stable cycle life of ≈2400 h at 1 mA cm-2. In particular, a full cell with LiFePO4 cathode provides a good capacity retention of 81.2% at 4 C after 600 cycles.
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Background: Protein-energy wasting (PEW) is a common complication in patients with peritoneal dialysis (PD). Few investigations involved risk factors identification and predictive model construction related to PEW. We aimed to develop a nomogram to predict PEW risk in patients with peritoneal dialysis. Methods: We collected data from end-stage renal disease (ESRD) patients who regularly underwent peritoneal dialysis between January 2011 and November 2022 at two hospitals retrospectively. The outcome of the nomogram was PEW. Multivariate logistic regression screened predictors and established a nomogram. We measured the predictive performance based on discrimination ability, calibration, and clinical utility. Evaluation indicators were receiver operating characteristic (ROC), calibrate curve, and decision curve analysis (DCA). The performance calculation of the internal validation cohort validated the nomogram. Results: In this study, 369 enrolled patients were divided into development (n = 210) and validation (n = 159) cohorts according to the proportion of 6:4. The incidence of PEW was 49.86%. Predictors were age, dialysis duration, glucose, C-reactive protein (CRP), creatinine clearance rate (Ccr), serum creatinine (Scr), serum calcium, and triglyceride (TG). These variables showed a good discriminate performance in development and validation cohorts (ROC = 0.769, 95% CI [0.705-0.832], ROC = 0.669, 95% CI [0.585-0.753]). This nomogram was adequately calibrated. The predicted probability was consistent with the observed outcome. Conclusion: This nomogram can predict the risk of PEW in patients with PD and provide valuable evidence for PEW prevention and decision-making.
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Diálisis Peritoneal , Diálisis Renal , Humanos , Nomogramas , Estudios Retrospectivos , Diálisis Peritoneal/efectos adversos , Fenómenos Físicos , CaquexiaRESUMEN
OBJECTIVE: To evaluate the prospective association between cumulative resting heart rate (cumRHR) and rapid renal function decline (RRFD) in a cohort of individuals aged 60 and older. METHODS: In the Tianjin Chronic Kidney Disease Cohort Study, the individuals who underwent three consecutive physical examinations between 2014 and 2017, with estimated glomerular filtration rate (eGFR) greater than 60 mL/min per 1.73 m2 and aged 60 years or older were enrolled. A total of 27,564 patients were prospectively followed up from January 1, 2017 to December 31, 2020. The 3-year cumRHR was calculated. The primary outcome was RRFD, defined as an annualized decline in eGFR of 5 mL/min per 1.73 m2 or greater. Logistic and restricted spline regression models and subgroup analysis were used to investigate the association of cumRHR with RRFD after adjusting for all confounders. RESULTS: During a median follow-up of 3.2 years, a total of 4,347 (15.77%) subjects developed RRFD. In fully-adjusted models, compared with the lowest quartile of cumRHR, the odds ratio (OR) for the highest was 1.44 (1.28-1.61), P < 0.001. Furthermore, each 1-standard deviation (27.97 beats/min per year) increment in cumRHR was associated with a 17% (P < 0.001) increased risk of RRFD, with a linear positive correlation (P for non-linear = 0.803). Participants with a 3-year cumRHR ≥ 207 (beats/min) * year (equivalent to ≥ 69 beats/min per year in 3 years) were found to be at a higher risk of RRFD. CONCLUSIONS: The cumRHR is significantly associated with a higher risk of RRFD among older adults. These results might provide an effective goal for managing and delaying the decline of renal function in the older adults.
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Objectives: There is paucity of studies to investigate the association between combined and long-term exposure to air pollution and the risk of incident chronic kidney disease (CKD) in older adults. Methods: A prospective cohort of 90,032 older adults who did not have CKD at baseline were followed up from January 1, 2017, to December 31, 2019. Various pollutant data, including particulate matter with diameters ≤ 2.5 mm (PM2.5), ≤ 10 mm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), Ozone (O3), and carbon monoxide (CO), from all monitoring stations in Binhai New Area, Tianjin were considered in calculating the mean exposure concentration of each pollutant over 2 years. By summing each pollutant concentration weighted by the regression coefficients, we developed an air pollution score that assesses the combined exposure of these air pollutants. Due to the strong correlation between air pollutants, Principal Component Analysis (PCA) score was also developed. The association between air pollutants and incident CKD in the elderly was analyzed. Results: A total of 90,032 subjects participated in this study with a median follow-up of 545 days. Among them, 22,336 (24.8%) developed CKD. The HR (95% CI) for air pollution score and incidence of CKD was 1.062 (1.060-1.063) and p <0.001 after adjusting for all confounders. The adjusted HRs for the quartile subgroups of combined air pollution score were: Q2: 1.064 (1.013-1.117); Q3: 1.141 (1.088-1.198); and Q4: 3.623 (3.482-3.770), respectively (p for trend <0.001). The adjusted HRs for the quartile subgroups of air quality index (AQI) were: Q2: 1.035 (0.985-1.086); Q3: 1.145 (1.091-1.201); and Q4: 3.603 (3.463-3.748), respectively (p for trend <0.001). When the risk score was over 86.9, it significantly rose in a steep curve. The subgroup analysis showed that male, younger or exercise were more likely to develop CKD. Conclusion: Combined air pollution score, AQI, and PCA score were associated with an increased risk of CKD in an exposure-response relationship. Our current results might also provide evidence for developing environmental protection policies.
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Contaminantes Atmosféricos , Contaminantes Ambientales , Ozono , Insuficiencia Renal Crónica , Anciano , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Monóxido de Carbono/análisis , Estudios de Cohortes , Contaminantes Ambientales/análisis , Humanos , Masculino , Dióxido de Nitrógeno/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , Estudios Prospectivos , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/etiología , Dióxido de Azufre/análisisRESUMEN
PURPOSE: To evaluate the effect of fluctuations in waist circumference (WC), weight, and body mass index (BMI) on the incidence of diabetes in older adults. PATIENTS AND METHODS: A prospective cohort of 61,587 older adults (age, 60-96 years) who did not have diabetes at study initiation was examined. Data on weight, BMI, and WC were collected, and participants were followed up until 31 December 2018. The main end point was new-onset diabetes. A Cox regression model was used to estimate the risk of diabetes (hazard ratios [HRs] and confidence intervals [CI]) in these participants. RESULTS: During a mean follow-up of 3.6 years, being overweight (HR [95% CI] 1.87 [1.62-2.17]), obesity (1.41 [1.26-1.59]), abdominal obesity (1.42 [1.28-1.58]), and obesity plus abdominal obesity at baseline (1.93 [1.66-2.25]) increased the risk of diabetes onset. Compared with older adults who "maintained normal WC", those who "remained abdominally obese" (HR = 1.66), "became abdominally obese" (HR = 1.58), or "achieved normal WC" (HR = 1.36) were at a higher risk of diabetes onset, as well as those with an increase in WC > 3 cm or > 5% compared with the baseline level. Weight gain or loss > 6 kg or weight gain > 5%, increase or decrease in BMI > 2 kg/m2, or an increase in BMI > 10% were associated with a higher diabetes risk. The diabetes risk was reduced by 19% in overweight older adults who exercised daily. CONCLUSION: For older adults, WC, BMI, and healthy weight maintenance reduce the diabetes risk. The findings may provide evidence for developing guidelines of proper weight and WC control for older adults.
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BACKGROUND: Research investigating the effect of air pollution on diabetes incidence is mostly conducted in Europe and the United States and often produces conflicting results. The link between meteorological factors and diabetes incidence remains to be explored. We aimed to explore associations between air pollution and diabetes incidence and to estimate the nonlinear and lag effects of meteorological factors on diabetes incidence. METHODS: Our study included 19,000 people aged ≥60 years from the Binhai New District without diabetes at baseline. The generalized additive model (GAM) and the distributed lag nonlinear model (DLNM) were used to explore the effect of air pollutants and meteorological factors on the incidence of diabetes. In the model combining the GAM and DLNM, the impact of each factor (delayed by 30 days) was first observed separately to select statistically significant factors, which were then incorporated into the final multivariate model. The association between air pollution and the incidence of diabetes was assessed in subgroups based on age, sex, and body mass index (BMI). RESULTS: We found that cumulative RRs for diabetes incidence were 1.026 (1.011-1.040), 1.019 (1.012-1.026), and 1.051 (1.019-1.083) per 10 µg/m3 increase in PM2.5, PM10, and NO2, respectively, as well as 1.156 (1.058-1.264) per 1 mg/m3 increase in CO in a single-pollutant model. Increased temperature, excessive humidity or dryness, and shortened sunshine duration were positively correlated with the incidence of diabetes in single-factor models. After adjusting for temperature, humidity, and sunshine, the risk of diabetes increased by 9.2% (95% confidence interval (CI):2.1%-16.8%) per 10 µg/m3 increase in PM2.5. We also found that women, the elderly (≥75 years), and obese subjects were more susceptible to the effect of PM2.5. CONCLUSION: Our data suggest that PM2.5 is positively correlated with the incidence of diabetes in the elderly, and the relationship between various meteorological factors and diabetes in the elderly is nonlinear.
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Contaminantes Atmosféricos , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Medición de Riesgo , Anciano , Contaminación del Aire , Presión Atmosférica , Índice de Masa Corporal , China/epidemiología , Exposición a Riesgos Ambientales , Femenino , Humanos , Humedad , Incidencia , Masculino , Conceptos Meteorológicos , Persona de Mediana Edad , Análisis Multivariante , Dinámicas no Lineales , Ozono , Material Particulado , Estaciones del Año , TemperaturaRESUMEN
OBJECTIVE: This study aimed to assess whether metabolically healthy obesity (MHO) increases the risk of diabetes and to explore how the occurrence of metabolic disorders affects the risk of diabetes and which factors determine metabolic health. METHODS: This study examined 49,702 older people without diabetes via the Binhai Health Screening Program in Tianjin. RESULTS: Compared with individuals with metabolic health and normal weight, the risk of diabetes was increased in older adults with MHO (hazard ratio [HR]: 1.786, 95% CI: 1.407-2.279) but was not significantly increased when metabolic health was characterized by the absence of metabolic abnormalities. The older adults who were initially affected by MHO and then converted to having an unhealthy phenotype had a higher diabetes risk than older individuals with stable and healthy normal weight (HR: 3.727, 95% CI: 2.721-5.105). Waist circumference was an independent predictor of the transition from a metabolically healthy status to an unhealthy status in all BMI categories (odds ratio: 1.059, 95% CI: 1.026-1.032). CONCLUSIONS: The MHO phenotype was associated with an increased incidence of diabetes in older adults. The presence of metabolic disorders in the group with MHO was associated with an increased diabetes risk and was predicted by the waist circumference at baseline.
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Diabetes Mellitus/epidemiología , Obesidad Metabólica Benigna/complicaciones , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad Metabólica Benigna/epidemiología , Fenotipo , Factores de Riesgo , Factores de TiempoRESUMEN
In this study, a new kinetic model of spontaneous liquid-gas imbibition (SLGI) for microporous adsorbents has been developed. With three carbon molecular sieves (CMS) as adsorbents, N2 as gas probe and water as liquid probe, the kinetics of spontaneous water-N2 imbibition in CMS has been investigated at atmospheric pressure, and the applicability of the kinetic model to the SLGI has been assessed. The influences of the particle size of CMS and the experimental temperature in the range of 20-35⯰C on the imbibition process have been analyzed based on the kinetic model. The relations between the kinetic parameters of the SLGI and the microporous parameters of the CMS obtained by CO2 adsorption at 273â¯K have been elucidated. The results indicate that the imbibition process is controlled by the diffusion of the water molecules into and N2 out of the micropores and the adsorption of the water on the pore surface of the CMS. The equilibrium gas recovery is positively related with the micropore volume, and the gas recovery rate depends mainly on the micropore size of the CMS.
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Sanguis draxonis (SD), also known as "Dragon's Blood", is a traditional herb medicine that has been used to treat a variety of complications with unknown mechanisms. Recent studies show that SD displays immunosuppressive activities and improves symptoms of type I diabetes in animal models. However, the mechanisms underlying SD's immunosuppressive actions are not completely understood. The voltage-gated Kv1.3 channel plays a critical role in the pathogenesis of autoimmune diseases by regulating the functions of both T cells and B cells. Here we investigated the effect of SD and one of its active components loureirin B (LrB) on Kv1.3. Both SD and LrB inhibited Kv1.3-mediated currents, produced a membrane depolarization, and reduced Ca(2+) influx in Jurkat T cells. In addition, application of LrB inhibited phytohemagglutinin (PHA)-induced IL-2 release from activated Jurkat T cells. Furthermore, point mutations in the selective filter region significantly reduced the inhibitory effect of LrB on Kv1.3. The results of these experiments provide evidence that LrB is a channel blocker of Kv1.3 by interacting with amino acid residues in its selective filter region. Direct inhibition of Kv1.3 in T cells by SD and LrB might be the cellular and molecular basis of SD-mediated immunosuppression.