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Eight previously undescribed diterpenoids, caesamins A-H (1-8), were separated and identified from the seeds of Caesalpinia minax Hance. Their structures were characterized by extensive spectroscopic data and X-ray crystallographic analysis. Structurally, caesamin A (1) is the first cassane-type diterpenoid with a C23 carbon skeleton containing an unusual isopropyl. Caesamin F (6) represents the first example of cleistanthane diterpenoid from the genus Caesalpinia. Caesamins B (2) and F (6) exhibited inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages with IC50 values of 45.67 ± 0.92 and 42.99 ± 0.24 µM, comparable to positive control 43.69 ± 2.62 µM of NG-Monomethyl-L-arginine. Furthermore, the chemotaxonomic significance of the isolates was discussed.
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Caesalpinia , Diterpenos , Óxido Nítrico , Semillas , Caesalpinia/química , Diterpenos/química , Diterpenos/farmacología , Diterpenos/aislamiento & purificación , Ratones , Semillas/química , Animales , Células RAW 264.7 , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Estructura Molecular , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.
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Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC50 value of 18.13 ± 0.63 µM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which was demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer.
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Proteínas Quinasas Activadas por AMP , Antineoplásicos Fitogénicos , Autofagia , Caesalpinia , Proliferación Celular , Diterpenos , Ensayos de Selección de Medicamentos Antitumorales , Diana Mecanicista del Complejo 1 de la Rapamicina , Neoplasias Pancreáticas , Especies Reactivas de Oxígeno , Semillas , Caesalpinia/química , Humanos , Diterpenos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Semillas/química , Autofagia/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Línea Celular Tumoral , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Objective @#Objective To investigate the demand for health management and influencing factors among occupational population at high risk of stroke, so as to provide insights into the development of stroke health management strategies among occupational population.@*Methods@#Occupational population aged 40 to 60 years who participated in health examination were sampled from three tertiary hospitals in Luzhou City, Sichuan Province using a quota sampling method in the ratio of 4∶1∶1, from August to December 2020. Participants' blood biochemistry tests and health examination were collected through the examination reports, and the participants at high risk of stroke were screened using the assessment criteria for high-risk of stroke. Participants' general information and demand for health management were collected using questionnaire surveys. In addition, factors affecting the demand for health management were identified using a multivariable logistic regression model. @*Results@#A total of 3 003 people who participated in health examination were investigated, and 1 062 participants met the assessment criteria for high risk of stroke, accounting for 35.36%. There were 1 000 men (94.16%) and 62 women (5.84%), with a mean age of (49.26±4.97) years. There were 414 professional and technical staff (39.50%). There were 709 participants (66.76%) with demand for health management, with the top three in the demand as health checkups (915 participants, accounting for 86.16%), health consultation (601 participants, accounting for 56.60%) and exercise guidance (560 participants, accounting for 52.73%), and 210 participants (19.77%) received health management. Multivariable logistic regression analysis showed that occupational population at high risk of stroke who received health management were more likely to have the demand for health management (OR=2.158, 95%CI: 1.479-3.149). @*Conclusions@#The occupational population at high risk of stroke have the demand for health management. Having received health management may affect the demand for health management among occupational population at high risk of stroke.
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Spinal cord injury (SCI) often leads to physical limitations, persistent pain, and major lifestyle shifts, enhancing the likelihood of prolonged psychological stress and associated disorders such as anxiety and depression. The mechanisms linking stress with regeneration remain elusive, despite understanding the detrimental impact of chronic stress on SCI recovery. In this study, we investigated the effect of chronic stress on primary sensory axon regeneration using a preconditioning lesions mouse model. Our data revealed that chronic stress-induced mitochondrial cristae loss and a decrease in oxidative phosphorylation (OXPHOS) within primary sensory neurons, impeding central axon regrowth. Corticosterone, a stress hormone, emerged as a pivotal player in this process, affecting satellite glial cells by reducing Kir4.1 expression. This led to increased neuronal hyperactivity and reactive oxygen species levels, which, in turn, deformed mitochondrial cristae and impaired OXPHOS, crucial for axonal regeneration. Our study underscores the need to manage psychological stress in patients with SCI for effective sensory-motor rehabilitation.
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Axones , Traumatismos de la Médula Espinal , Humanos , Ratones , Animales , Axones/metabolismo , Regeneración Nerviosa/fisiología , Fosforilación Oxidativa , Neuronas/metabolismo , Traumatismos de la Médula Espinal/patologíaRESUMEN
Lupus nephritis (LN) is a major cause death in patients with systemic lupus erythematosus. We aimed to find the differentially expressed genes (DEGs) in LN and confirm the regulatory mechanism on LN. The mouse model of LN was constructed by subcutaneous injection of pristane. RNA-seq screened 392 up-regulated and 447 down-regulated DEGs in LN mouse model, and KEGG analysis found that the top 20 DEGs were enriched in arachidonic acid metabolism, tryptophan metabolism, etc. The hub genes, Kynu, Spidr, Gbp3, Cbr1, Cyp4b1, and Cndp2 were identified, in which Gbp3 was selected for following study. Afterwards, the function of Gbp3 on the proliferation, inflammation, and pyroptosis of LN was verified by CCK-8, ELISA, and WB in vitro. The results demonstrated that si-Gbp3 promoted cell proliferation and inhibited the levels of inflammatory factors (IL-1ß, TNF-α and IL-8) and pyroptosis-related proteins (GSDMD, Caspase-1 and NLRP3) in a cell model of LN. In constrast, Gbp3 overexpression played an opposite role. In summary, Gbp3 promoted the progression of LN via inhibiting cell proliferation and facilitating inflammation and pyroptosis.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Animales , Ratones , Nefritis Lúpica/genética , Piroptosis , Inflamación/genética , Proliferación Celular , Modelos Animales de Enfermedad , Proteínas de Unión al GTPRESUMEN
INTRODUCTION: Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease in adults that is associated with significant joint issues and systemic inflammation. One of the signs of bone damage in RA is osteoporosis (OP). Leptin is an inflammatory protein that has been reported to be related to RA. The potential relationships among leptin, disease activity, and OP in Chinese patients with RA are not well known. METHODS: In total, 245 patients with RA and 120 healthy controls were included in this study. Detailed data on the clinical characteristics and laboratory features were collected. Information about physical activity and functional status was recorded using specific questionnaires. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). The MECALL castor-50-hf model X-ray scanner was used for the two-hand (including wrist) photographs. RESULTS: Serum leptin levels differed significantly between the RA group and healthy control subjects (1.27/3.29 vs. 0.17/0.24, Z=13.29, P<0.001). The positive rate of leptin protein in RA patients was 86.35%, which was higher than that in controls (19.55%) (χ2=28.51, P<0.001). Pearson's correlation test showed that morning stiffness, disease duration, joint swelling, joint tenderness, swollen joint count (SJC), tender joint count (TJC), health assessment questionnaire (HAQ) score, and Sharp-van der Heijde method (Sharp) score were positively correlated with the level of serum leptin (r=0.212, r=0.312, r=0.322, r=0.501, r=0.291, r=0.334, P<0.05). There was a clear increasing trend in the level of serum leptin according to the different disease activity scores and in the 28 joint activity (DAS28) groups (F=13.936, P<0.001). Elevated leptin was a risk factor for increased disease activity and OP according to logistic regression analysis. The median leptin level differed significantly between the normal bone mass group, osteopenia group, and OP group (P<0.001). An increased serum leptin level was a risk factor for RA-induced osteoporosis according to logistic regression analysis (P<0.001). CONCLUSION: These results suggest that the level of serum leptin is associated with disease activity and secondary OP among Chinese patients with RA. Key Points ⢠Serum leptin levels in RA patients are higher than those in normal control group. ⢠Leptin was associated with disease activity. ⢠Leptin was associated with the occurrence of systemic osteoporosis and affects bone erosion in RA patients.
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Artritis Reumatoide , Leptina , Osteoporosis , Adulto , Humanos , Absorciometría de Fotón , Artritis Reumatoide/complicaciones , Densidad Ósea , Pueblos del Este de Asia , Leptina/sangre , Osteoporosis/complicacionesRESUMEN
Objective@#To evaluate the effectiveness of sex education curriculum on sex related knowledge, attitude and practice of preschool children in senior class, so as to provide a reference basis for the comprehensive development of early childhood sex education in the future.@*Methods@#From December 2021 to July 2022, the two stage stratified sampling method was used to select 12 kindergartens in Luzhou City, of which 6 senior classes were chosen as the intervention group (360 before the intervention, 354 after the intervention), and the other 6 senior classes as the control group (416 before the intervention, 326 after the intervention). The intervention group was conducted with early childhood sex education classes in the form of a series of courses, with a total of four topics including one parent course and three child courses every month, while the control group received routine teaching schedule. A survey was conducted on the knowledge, attitude and practice of early childhood sex education among preschool children and their parents before and after the intervention. χ 2 text analysis was used to carry out the effect.@*Results@#There was no statistically significant difference in sexual education related knowledge, attitude and practice between the intervention group and the control group before intervention ( P >0.05). There were statistically significant differences in the awareness rate of sexual knowledge (77.4%, 69.6%), positive attitude rate (73.7%, 10.1%), good practice rate (59.3%, 38.0%), and good knowledge, attitude and practice rate (37.9%,1.8%) between the intervention group and the control group after intervention ( χ 2=5.28, 279.77, 30.77, 134.62, P <0.05). Similar findings were observed in the intervention group before and after the intervention ( χ 2=63.39, 344.31 , 41.41, 161.03, P <0.05). The difference in the awareness rate of sexual related knowledge between the control group before and after intervention was statistically significant ( χ 2=44.29, P <0.05).@*Conclusion@#The early childhood sex education curriculum might help improve sex related knowledge, attitude and practice. Kindergartens should be encouraged to actively promote sex education, training, and guidance for preschool children and their parents, in order to improve the sex related knowledge, attitude and practice.
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Objective@#To understand the consistency and factors influencing rural parents knowledge, attitude and practice about early childhood sex education, so as to put forward effective suggestions and countermeasures for improving childhood sex education in rural areas.@*Methods@#A multi stage stratified sampling method was used to investigate the knowledge, attitude and practice of early childhood sex education among 1 015 parents in 16 kindergartens in rural areas of Sichuan from March to May 2019. Chi square text and multivariate Logistic regression analysis were used to analyze factors affecting the consistency of parents knowledge, attitude and practice of childhood sex education.@*Results@#Nearly 64.9%, 85.9% and 44.7% of parents with sufficient knowledge, support, and implement of early children s sex education, respectively, and the consistency rate of knowledge, attitude and practice were 30.2%. The results of the multivariate Logistic regression analysis showed that parents aged <31 years ( OR= 5.35 , 95%CI =2.93-9.77), 31-40 years ( OR=4.82, 95%CI =2.65-8.76) and 41-50 years ( OR=2.37, 95%CI =1.10-5.11), and the mother s education level being middle school ( OR=3.67, 95%CI =1.75-7.69), secondary/high school ( OR=2.83, 95%CI =1.32-6.05) and college/bachelor s degree and above ( OR=5.44, 95%CI =2.23-12.98), sex related questions asked by child ( OR=2.00, 95%CI =1.44-2.78), having sex education in the family ( OR=5.38, 95% CI =3.82-7.59), believing that parents should be responsible for sex education for young children ( OR=2.58, 95%CI =1.40-4.74) had a higher consistency rate of knowledge, attitude and practice in early childhood sex education ( P <0.05).@*Conclusion@#In rural areas of Sichuan, although parents highly support early childhood sex education, the eligible rate of knowledge and the implementing rate are quite low, as well as the consistent rate of knowledge, attitude and practice. Relevant departments should pay attention to strengthen publicity and education, especially among older parents, low educated parents and those opposed to or not yet implementing child sex education.
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INTRODUCTION: Malaria importation can be caused by cross-border movement either of both people and anopheline mosquitoes. However, there still lacks robust evidence of imported malaria caused by Plasmodium spp. infected anopheles along international border areas (border-spill malaria). The objectives of this study were to confirm whether an outbreak of Plasmodium vivax malaria is border-spill malaria and assess the effects of China's public health response along China-Myanmar border. METHODS: Epidemiological, parasitological and entomological investigations were conducted to investigate the outbreak of border-spill malaria. Meanwhile, comprehensive interventions were carried out to prevent further transmission and reintroduction of malaria. RESULTS: Rapid diagnostic testing, microscopy and polymerase chain reaction were performed and the infections were confirmed as P. vivax. A total of 22 (9.21%) of 239 workers contracted P. vivax during the outbreak. Multivariate logistic regression analysis identified that the distance of worker shelters in China within 300 meters to the internally displaced person (IDP) camps in Myanmar was a risk factors associated with malaria infection (adjusted odds ratio 7.5920; 95% confidence interval, 2.6079-22.1013; P = 0.0002). After comprehensive interventions, malaria transmission was successfully interpreted and prevented at the project site till the completion of project on 14 January 2020, and recurrence of P. vivax malaria was not detected by the end of 2020. CONCLUSION: This study provided robust evidence of border-spill malaria along China-Myanmar border. Malaria parasite reservoir and distance travelled by female anopheline mosquitoes are two determinants for border-spill malaria. The public health response to the outbreak indicates that the malaria surveillance and response system works well in preventing reintroduction of malaria. However, prevention of border-spill malaria is still a major challenge in the Yunnan border area, China.
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Anopheles , Malaria Vivax , Malaria , Animales , Femenino , Humanos , Salud Pública , Mianmar/epidemiología , China/epidemiología , Malaria Vivax/parasitología , Malaria/epidemiología , Brotes de Enfermedades , Plasmodium vivaxRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies are shown to be effective therapeutics for providing coronavirus disease 2019 (COVID-19) protection. However, recurrent variants arise and facilitate significant escape from current antibody therapeutics. Bispecific antibodies (bsAbs) represent a unique platform to increase antibody breadth and to reduce neutralization escape. Herein, a novel immunoglobulin G-variable domains of heavy-chain-only antibody (IgG-VHH) format bsAb derived from a potent human antibody R15-F7 and a humanized nanobody P14-F8-35 are rationally engineered. The resulting bsAb SYZJ001 efficiently neutralizes wild-type SARS-CoV-2 as well as the alpha, beta, gamma, and delta variants, with superior efficacy to its parental antibodies. Cryo-electron microscopy structural analysis reveals that R15-F7 and P14-F8-35 bind to nonoverlapping epitopes within the RBD and sterically hindered ACE2 receptor binding. Most importantly, SYZJ001 shows potent prophylactic and therapeutic efficacy against SARS-CoV-2 in three established mouse models. Collectively, the current results demonstrate that the novel bsAb format is feasible and effective, suggesting great potential as an inspiring antiviral strategy.
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Anticuerpos Biespecíficos , COVID-19 , Ratones , Animales , Humanos , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Inmunoglobulina G/genética , Anticuerpos Biespecíficos/farmacología , Microscopía por Crioelectrón , Anticuerpos Antivirales/uso terapéuticoRESUMEN
Sepsis-associated encephalopathy (SAE), the most popular cause of coma in the intensive care unit (ICU), is the diffuse cerebral damage caused by the septic challenge. SAE is closely related to high mortality and extended cognitive impairment in patients in septic shock. At present, many studies have demonstrated that SAE might be mainly associated with blood-brain barrier damage, abnormal neurotransmitter secretion, oxidative stress, and neuroimmune dysfunction. Nevertheless, the precise mechanism which initiates SAE and contributes to the long-term cognitive impairment remains largely unknown. Recently, a growing body of evidence has indicated that there is close crosstalk between SAE and peripheral immunity. The excessive migration of peripheral immune cells to the brain, the activation of glia, and resulting dysfunction of the central immune system are the main causes of septic nerve damage. This study reviews the update on the pathogenesis of septic encephalopathy, focusing on the over-activation of immune cells in the central nervous system (CNS) and the "neurocentral-endocrine-immune" networks in the development of SAE, aiming to further understand the potential mechanism of SAE and provide new targets for diagnosis and management of septic complications.
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In this work, we consider the inelastic scattering of incident electrons as a key process for analyzing the significant differences in secondary electron (SE) emission between diamond and graphite. Dielectric functions and energy- and momentum-dependent energy loss functions were obtained by first-principle calculations. These were then used to calculate the inelastic mean free path (IMFP) and stopping power in different directions. The results show that the properties of diamond are very close in different directions, and its IMFP is lower than that of graphite when the electron energy is higher than 30 eV. In graphite, the incident electrons may exhibit directional preferences in their motion. These results indicate that, in graphite, SEs are excited in deeper positions than in diamond, and more SEs move in a horizontal direction than in a vertical direction, which leads to the difference in secondary electron yield (SEY).
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The PALB2 tumor suppressor plays key roles in DNA repair and has been implicated in redox homeostasis. Autophagy maintains mitochondrial quality, mitigates oxidative stress and suppresses neurodegeneration. Here we show that Palb2 deletion in the mouse brain leads to mild motor deficits and that co-deletion of Palb2 with the essential autophagy gene Atg7 accelerates and exacerbates neurodegeneration induced by ATG7 loss. Palb2 deletion leads to elevated DNA damage, oxidative stress and mitochondrial markers, especially in Purkinje cells, and co-deletion of Palb2 and Atg7 results in accelerated Purkinje cell loss. Further analyses suggest that the accelerated Purkinje cell loss and severe neurodegeneration in the double deletion mice are due to excessive oxidative stress and mitochondrial dysfunction, rather than DNA damage, and partially dependent on p53 activity. Our studies uncover a role of PALB2 in mitochondrial homeostasis and a cooperation between PALB2 and ATG7/autophagy in maintaining redox and mitochondrial homeostasis essential for neuronal survival.
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Autofagia , Mitocondrias , Animales , Autofagia/genética , Proteína 7 Relacionada con la Autofagia/genética , Encéfalo/metabolismo , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Homeostasis/genética , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Oxidación-ReducciónRESUMEN
Identifying the health risk of PM2.5 is essential for urban air pollution control. In 2013, China announced the ever-strict national Air Pollution Prevention and Control Action Plan, and its health benefit should be evaluated to provide reference for future policymaking. In this study, we conducted a seven-year (2014-2020) continuous observation of PM2.5 in Shenzhen, the third largest city in China, which has relatively good air quality. The results showed that the annual mean PM2.5 and total concentration of 21 associated metals dropped from 37.7 to 18.5 µg/m3 and from 2.4 to 1.1 µg/m3, respectively. Combining methods for source apportionment and health risk assessment, we found that the total carcinogenic risk (CR) of five hazardous metals (Cd, Cr, Ni, Co, and Pb) showed a clear decreasing trend. However, the total CR (1.8 × 10-6) in 2020 still exceeded the widely acceptable risk level (i.e., 1 × 10-6), with the primary contributor changing from industrial emissions (61%) to vehicle emissions (63%). Further analysis indicated that the CR of vehicles mainly came from Cr and Ni released by braking and tire wearing and has fluctuated in recent years, highlighting a great challenge of controlling nonexhaust emissions of vehicles (including electric cars) in the future.
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Contaminantes Atmosféricos , Contaminación del Aire , Metales Pesados , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Carcinógenos , China , Monitoreo del Ambiente/métodos , Metales/análisis , Material Particulado/análisis , Medición de Riesgo , Emisiones de Vehículos/análisisRESUMEN
α-Synuclein is a key protein in the pathogenesis of Parkinson's disease as it accumulates in fibrillar form in affected brain regions. Misfolded α-synuclein seeds recruit monomeric α-synuclein to form aggregates, which can spread to anatomically connected brain regions, a phenomenon that correlates with clinical disease progression. Thus, downregulating α-synuclein levels could reduce seeding and inhibit aggregate formation and propagation. We previously reported that microRNA-7 (miR-7) protects neuronal cells by downregulating α-synuclein expression through its effect on the 3'-untranslated region of SNCA mRNA; however, whether miR-7 blocks α-synuclein seeding and propagation in vivo remains unknown. Here, we induced miR-7 overexpression in the mouse striatum unilaterally by infusing adeno-associated virus 1 (AAV-miR-7) followed by inoculation with recombinant α-synuclein preformed fibrils (PFF) a month later. Compared with control mice injected with non-targeting AAV-miR-NT followed by PFF, AAV-miR-7 pre-injected mice exhibited lower levels of monomeric and high-molecular-weight α-synuclein species in the striatum, and reduced amount of phosphorylated α-synuclein in the striatum and in nigral dopamine neurons. Accordingly, AAV-miR-7-injected mice had less pronounced degeneration of the nigrostriatal pathway and better behavioral performance. The neuroinflammatory reaction to α-synuclein PFF inoculation was also significantly attenuated. These data suggest that miR-7 inhibits the formation and propagation of pathological α-synuclein and protects against neurodegeneration induced by PFF. Collectively, these findings support the potential of miR-7 as a disease modifying biologic agent for Parkinson's disease and related α-synucleinopathies.
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MicroARNs , Enfermedades Neurodegenerativas/genética , Sinucleinopatías , Animales , Encéfalo/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Obesity has become an epidemic in several regions globally; it may lead to cardiovascular diseases, diabetes, and dyslipidemia. Despite many therapies, all bariatric procedures fail in some patients. There is a lack of literature comparing treatment effects on specific metabolic indexes. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant articles. GeMTC and R software were used to perform a network meta-analysis, draw forest plots, investigate the possibility of statistical heterogeneity, generate I2 statistics, rank probabilities, and evaluate relative effects of surgical procedures. All analyses were based on a Bayesian consistency model. We included 35 randomized controlled trials, comprising 2198 individuals and 13 interventions. For patients with high insulin resistance, single-anastomosis (mini-) gastric bypass (SAGB) and sleeve gastrectomy (SG) may be effective options, with mean differences (95% confidence intervals [CIs]) of -4.45 (-9.04 to -.34) and -4.23 (-6.74 to -2.22), respectively, compared with control groups. For patients with severe dyslipidemia, in addition to SAGB and SG, duodenal switch (DS) may be an effective surgery, with mean differences (95% CIs) of -.97 (-1.39 to -.55), -1.98 (-3.76 to -.19), .53 (.04 to 1.04), and -.94 (-1.66 to -.16) compared with control groups in terms of triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) concentrations, respectively. In adult overweight patients with or without diabetes, SAGB and SG are most effective at ameliorating insulin resistance. SAGB, Roux-en-Y gastric bypass + omentectomy, and DS are useful for reducing triglycerides, total cholesterol, and LDL-C. SG + omentectomy elevates HDL-C concentrations best. Adjustable gastric band and biliopancreatic diversion may not control insulin resistance or dyslipidemia well.
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Cirugía Bariátrica , Diabetes Mellitus Tipo 2 , Dislipidemias , Resistencia a la Insulina , Adulto , Teorema de Bayes , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/cirugía , Dislipidemias/complicaciones , Humanos , Metaanálisis en Red , ObesidadRESUMEN
The inherent features of covalent organic frameworks (COFs) make them highly attractive for uranium recovery applications. A key aspect yet to be explored is how to improve the selectivity and efficiency of COFs for recovering uranium from seawater. To achieve this goal, a series of robust and hydrophilic benzoxazole-based COFs is developed (denoted as Tp-DBD, Bd-DBD, and Hb-DBD) as efficient adsorbents for photo-enhanced targeted uranium recovery. Benefiting from the hydroxyl groups and the formation of benzoxazole rings, the hydrophilic Tp-DBD shows outstanding stability and chemical reduction properties. Meanwhile, the synergistic effect of the hydroxyl groups and the benzoxazole rings in the π-conjugated frameworks significantly decrease the optical band gap, and improve the affinity and capacity to uranium recovery. In seawater, the adsorption capacity of uranium is 19.2× that of vanadium, a main interfering metal in uranium extraction.
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Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19 , Epítopos/inmunología , SARS-CoV-2/inmunología , Anticuerpos de Cadena Única/inmunología , Animales , Anticuerpos Neutralizantes/farmacología , Anticuerpos Antivirales/farmacología , COVID-19/inmunología , COVID-19/prevención & control , Chlorocebus aethiops , Modelos Animales de Enfermedad , Humanos , Anticuerpos de Cadena Única/farmacología , Células VeroRESUMEN
This article explores the pathogenesis of sepsis AKI, and seeks to protect the acute damage of sepsis tissues and organs. This study is to prepare a rat sepsis-induced AKI model by CLP, and to observe the pathological changes of kidney tissue and the function of kidney changes, and observe the effect of siRNA nanoparticles on its intervention, preliminary explore the protective effect and possible mechanism of siRNA nanoparticles on AKI in sepsis rats, and provide more information for the clinical treatment of siRNA nanoparticles in sepsis theoretical and experimental basis. We analysis the benefit and deficiency of nuclear factor-κB (NF-κB) activation in the pathogenesis of glomerulonephritis and its regulatory effect on NF-κB activation. In the rat model group, no treatment was given after injection of nephrotoxic serum, and the rats were sacrificed on the 14th day; the compound siRNA nanoparticle intervention group (treatment group) was given dexamethasone 0.125 daily on the 1st to 14th day after nephrotoxic serum injection. Immunohistochemistry and medical image analysis system were used to observe NF-κB activation of monocyte chemotactic protein-1 (MCP-1) in glomeruli and tubules, and analyze their relationship with proteinuria and glomerular cells. The results showed that the expression of NF-κB in the glomeruli and tubules of the model group was significantly up-regulated regarding to the control group, and MCP-1's expression in the glomeruli and tubules of the model group was higher than that of the control group. The activation of NF-κB and the expression of MCP-1 in glomeruli are closely related to monocyte infiltration and proteinuria; NF-κB activation and MCP-1 expression in glomeruli and tubules of the compound siRNA nanoparticles intervention group were significantly down-regulated. It was concluded that the activation of NF-κB has great impact on the pathogenesis of glomerulonephritis, and inhibition of NF-κB activation may be one of the mechanisms of anti-nephritis effect.