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This study outlines asthma burden trends across age, sex, regions and risk factors in 'Belt and Road' (B&R) countries from 1990 to 2019 using the Global Burden of Disease Study 2019 data. Incidence, mortality, prevalence, years lived with disability (YLDs), disability-adjusted life years (DALYs) and risk factors for asthma were measured. India, China and Indonesia bore the heaviest burden in 2019. Despite the significant decline in the average annual percent change for age-standardized mortality and years of life lost from 1990 to 2019, increases were observed in several East Asian, Central Asian, North African and Middle Eastern countries between 2010 and 2019. For both sexes, YLDs decreased in most B&R countries but increased in Montenegro, Saudi Arabia, Armenia, Vietnam and Oman. YLDs in Georgia, the United Arab Emirates and Albania increased in males but decreased in females. YLDs increased for those aged <15 years in Central Asia and Europe, while China's 50-74-year age group showed the lowest YLD change. High body mass index (BMI) led to increased YLDs in East, Central and Southeast Asia; North Africa; and the Middle East. Conclusively, asthma burden varies significantly by country. Tailoring control efforts to specific regions, sex and high BMI could enhance asthma management.

Asunto(s)

Asma , Años de Vida Ajustados por Discapacidad , Carga Global de Enfermedades , Humanos , Asma/epidemiología , Masculino , Femenino , Carga Global de Enfermedades/tendencias , Persona de Mediana Edad , Factores de Riesgo , Adulto , Adolescente , Anciano , Niño , Preescolar , Adulto Joven , Años de Vida Ajustados por Discapacidad/tendencias , Prevalencia , Lactante , Incidencia , Costo de Enfermedad , Salud Global/estadística & datos numéricos , Años de Vida Ajustados por Calidad de Vida , Recién Nacido

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To explore the influence of storage temperature and time on the stability of different concentrations of hepatitis C virus nucleic acid (HCV RNA) samples and to provide data reference for laboratory quality control. Serum samples of 10 patients with HCV RNA detection quantitation of 106-108 IU/mL were collected. The samples of each patient were diluted into three concentrations: high, medium, and low. Then the samples of each concentration were divided into 21, which were divided into three groups according to the storage conditions of -20°C, 4°C, and 25°C, with seven samples in each group. The samples were selected from each group for quantitative detection of HCV RNA on day 0, day 1, day 3, day 5, day 7, day 14, and day 30. The results of each concentration and storage temperature sample remained stable within 5 days. Based on the mixed-effect linear model, the main effects of temperature, time, and concentration were statistically significant (P < 0.01). There was an interaction effect between concentration and time (P = 0.0448), and there was also an interaction effect between temperature and time (P < 0.01). There was no interaction effect between concentration and temperature (P = 0.11) or between concentration, temperature, and time (P = 0.90). The results of serum samples with different concentrations of the HCV RNA remained stable within 5 days. The lower the initial concentration of HCV RNA serum sample, the worse the stability; the higher the storage temperature, the worse the stability. If conditions permit, the laboratory should store such samples at -20°C. IMPORTANCE: Previously, there were few reports about the influence of different concentrations of sample nucleic acid on the stability of samples at various temperatures and times in various literatures. Therefore, it is necessary to analyze the influence of concentration factors on the stability of samples and test results at different storage times and temperatures. This study took the concentration of hepatitis C virus nucleic acid as the research object to further understand the stability of hepatitis C virus nucleic acid test samples under various storage conditions, to provide data reference for the treatment of hepatitis C virus nucleic acid and RNA test samples before clinical laboratory test, and provide guidance and help for the improvement of laboratory quality control.

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Objective: To explore the value of metagenomic next-generation sequencing (mNGS) and culture in microbial diagnosis of patients with acute infection. Methods: We retrospectively analyzed 206 specimens from 163 patients who were admitted to the emergency department of The First Affiliated Hospital of Sun Yat-sen University between July 2020, and July 2021. We evaluated the diagnostic efficacy of mNGS and in-hospital traditional culture. Results: The total positive rate of mNGS was significantly higher than that culture methods (71.4 % vs 40.8 %, p < 0.001), while the sensitivity and accuracy of mNGS were found to be 92.9 % and 88.2 % respectively. However, culture exhibited superior specificity with a value of 92.6 % compared to 75.9 % for mNGS. The detection efficiency of mNGS and culture for fungi was comparable, but mNGS showed superior performance for bacterial detection. In the analysis of sepsis samples, mNGS outperformed traditional culture methods in diagnosing various types of samples, especially for sputum and bronchoalveolar lavage fluid. Among the identified infections, bacterial infections were the most common single infection (37.5 %). Additionally, bacterial-fungal infections represented the most prevalent form of mixed infection (77.3 %). Candida albicans and Staphylococcus aureus were identified as the predominant pathogens in the survival and death groups, respectively. No significant differences in microbial diversity were observed. Conclusion: Compared to culture methods, mNGS demonstrates superior positive rates, sensitivity, and accuracy in the rapid detection of acute infections, particularly in critically ill patients such as those with sepsis. This capability establishes a foundation for the swift and precise identification of pathogens, allowing for the analysis of clinical indicators and patient prognosis based on the extensive data generated from mNGS.

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Drug combinations have emerged as a promising therapeutic approach in cancer treatment, aimed at overcoming drug resistance and improving the efficacy of monotherapy regimens. However, identifying effective drug combinations has traditionally been time-consuming and often dependent on chance discoveries. Therefore, there is an urgent need to explore alternative strategies to support experimental research. In this study, we propose network-based prediction models to identify potential drug combinations for 11 types of cancer. Our approach involves extracting 55,299 associations from literature and constructing human protein interactomes for each cancer type. To predict drug combinations, we measure the proximity of drug-drug relationships within the network and employ a correlation clustering framework to detect functional communities. Finally, we identify 61,754 drug combinations. Furthermore, we analyze the network configurations specific to different cancer types and identify 30 key genes and 21 pathways. The performance of these models is subsequently assessed through in vitro assays, which exhibit a significant level of agreement. These findings represent a valuable contribution to the development of network-based drug combination design strategies, presenting potential solutions to overcome drug resistance and enhance cancer treatment outcomes.

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Background: The clinical presentation of Community-acquired pneumonia (CAP) in hospitalized patients exhibits heterogeneity. Inflammation and immune responses play significant roles in CAP development. However, research on immunophenotypes in CAP patients is limited, with few machine learning (ML) models analyzing immune indicators. Methods: A retrospective cohort study was conducted at Xinhua Hospital, affiliated with Shanghai Jiaotong University. Patients meeting predefined criteria were included and unsupervised clustering was used to identify phenotypes. Patients with distinct phenotypes were also compared in different outcomes. By machine learning methods, we comprehensively assess the disease severity of CAP patients. Results: A total of 1156 CAP patients were included in this research. In the training cohort (n=809), we identified three immune phenotypes among patients: Phenotype A (42.0%), Phenotype B (40.2%), and Phenotype C (17.8%), with Phenotype C corresponding to more severe disease. Similar results can be observed in the validation cohort. The optimal prognostic model, SuperPC, achieved the highest average C-index of 0.859. For predicting CAP severity, the random forest model was highly accurate, with C-index of 0.998 and 0.794 in training and validation cohorts, respectively. Conclusion: CAP patients can be categorized into three distinct immune phenotypes, each with prognostic relevance. Machine learning exhibits potential in predicting mortality and disease severity in CAP patients by leveraging clinical immunological data. Further external validation studies are crucial to confirm applicability.

Asunto(s)

Infecciones Comunitarias Adquiridas , Aprendizaje Automático , Fenotipo , Neumonía , Humanos , Infecciones Comunitarias Adquiridas/inmunología , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/mortalidad , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Neumonía/inmunología , Neumonía/diagnóstico , Neumonía/mortalidad , Anciano , Medición de Riesgo , Índice de Severidad de la Enfermedad , Adulto , Inmunofenotipificación

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Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.

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Cardiotónicos , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Piridinas , Humanos , Animales , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Piridinas/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Relación Estructura-Actividad , Cardiotónicos/farmacología , Cardiotónicos/química , Cardiotónicos/síntesis química , Cardiotónicos/uso terapéutico , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Masculino , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Ratones Desnudos , Descubrimiento de Drogas

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Compared with young liver donors, aged liver donors are more susceptible to ischemia-reperfusion injury (IRI) following transplantation, which may be related to excessive inflammatory response and macrophage dysfunction, but the specific mechanism is unclear. Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, and plays an important regulatory role in inflammation response and macrophage function regulation. But its role in IRI following aged-donor liver transplantation is still unclear. This study demonstrates that MSR1 expression is decreased in macrophages from aged donor livers, inhibiting their efferocytosis and pro-resolving polarisation. Decreased MSR1 is responsible for the more severe IRI suffered by aged donor livers. Overexpression of MSR1 using F4/80-labelled AAV9 improved intrahepatic macrophage efferocytosis and promoted pro-resolving polarisation, ultimately ameliorating IRI following aged-donor liver transplantation. In vitro co-culture experiments further showed that overexpression of MSR1 promoted an increase in calcium concentration, which further activated the PI3K-AKT-GSK3ß pathway, and induced the upregulation of ß-catenin. Overall, MSR1-dependent efferocytosis promoted the pro-resolving polarisation of macrophages through the PI3K-AKT-GSK3ß pathway-induced up-regulating of ß-catenin leading to improved IRI following aged-donor liver transplantation.

Asunto(s)

Trasplante de Hígado , Macrófagos , Ratones Endogámicos C57BL , Fagocitosis , Daño por Reperfusión , Receptores Depuradores de Clase A , Animales , Trasplante de Hígado/métodos , Trasplante de Hígado/efectos adversos , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/genética , Ratones , Macrófagos/metabolismo , Masculino , Receptores Depuradores de Clase A/metabolismo , Receptores Depuradores de Clase A/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hígado/metabolismo , Hígado/patología , Transducción de Señal , Donantes de Tejidos , Eferocitosis

RESUMEN

OBJECTIVE: To investigate the prognostic value of lymphocyte-to-monocyte ratio (LMR) and CD163+tumor-associated macrophages (TAM) in patients with diffuse large B cell lymphoma (DLBCL). METHODS: Peripheral blood and lymph node tissues were collected from 63 newly diagnosed DLBCL patients. LMR was calculated by the number of lymphocytes and monocytes in peripheral blood from the result of blood routine examination. The level of CD163+TAM in lymph nodes was detected by immunohistochemistry. The cut-off values of LMR and CD163+TAM were determined by ROC curves, and the prognostic value of LMR and CD163+TAM in DLBCL patients was analyzed. RESULTS: The LMR level of 63 newly diagnosed DLBCL patients was 3.69±1.71, and the median value of CD163+TAM was 26/HPF. The number of CD163+TAM was negatively correlated with LMR (r =-0.58) and positively correlated with monocyte count (r =0.46). The cut-off values of LMR and CD163+TAM determined by ROC curve were 2.95 and 29/HPF, respectively, and based on this, the patients were divided into low LMR group and high LMR group, as well as low CD163+TAM group and high CD163+TAM group. The proportion of patients with clinical stage III-IV, IPI score 3-5 and bone marrow infiltration in the low LMR group were higher than those in the high LMR group (P < 0.05). The proportion of patients with clinical stage III-IV, IPI score 3-5, elevated LDH level and bone marrow infiltration in the high CD163+TAM group were higher than those in the low CD163+TAM group (P < 0.05). There was a positive correlation between LMR and OS (r =0.43) and a negative correlation between CD163+TAM and OS (r =-0.65). DLBCL patients with low LMR and high CD163+TAM had shorter OS (P < 0.05). CONCLUSION: Low LMR and high CD163+TAM can be used as biological markers for poor prognosis of DLBCL patients.

Asunto(s)

Antígenos CD , Antígenos de Diferenciación Mielomonocítica , Linfoma de Células B Grandes Difuso , Monocitos , Receptores de Superficie Celular , Humanos , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Receptores de Superficie Celular/metabolismo , Pronóstico , Monocitos/metabolismo , Linfocitos , Macrófagos Asociados a Tumores/metabolismo , Ganglios Linfáticos/patología

RESUMEN

Based on the observation data of O3 concentration in Yinchuan in 2022, the monthly variation characteristics of O3 concentrations were analyzed. Further, based on the observation data of meteorological elements, conventional pollutants, and volatile organic compounds （VOCs） concentrations at an urban site in Yinchuan from May to July, the difference in meteorological elements and precursor concentrations between the polluted days and the non-polluted days were compared. Then, the O3 sensitivity and the VOCs sources were discussed using the Framework for 0-D Atmospheric Modeling （F0AM） and positive matrix factorization （PMF） model, respectively. The results showed that： ① The O3 pollution occurred from May to July in 2022, and the concentrations of O3-8h-90per were 156 µg·m-3, 170 µg·m-3, and 174 µg·m-3, respectively, with exceeding standard rates of 9.7%, 26.7%, and 29.0%, respectively. ② Compared with those on the non-polluted days, the hourly mean values of temperature, total solar radiation, and concentrations of various precursors on the O3-polluted days increased, including the volume concentrations of propane, isobutane, ethane, n-butane, and dichloromethane, which increased significantly by 33.1%, 29.1%, 25.0%, 22.7%, and 21.3%, respectively. The results showed that the combined increase in pollutant emissions and adverse meteorological conditions contributed to the formation of O3. ③ From May to July 2022, the top five VOCs species in terms of ozone formation potential （OFP） value on whole, non-polluted, and polluted days were the same. They were acetaldehyde, m/p-xylene, ethylene, isoprene, and toluene, mainly from solvent use sources, natural sources, and chemical industry emissions. ④ The local O3 production was mostly controlled by VOCs, and the relative incremental reactivity （RIR） results revealed that O3 production showed strong positive sensitivity to alkene and aromatic hydrocarbon but showed negative sensitivity to NOx on both polluted and non-polluted days. The relative contributions of active species such as acetone, ethylene, and isobutane to O3 production were high, and the implementation of an emission reduction scheme with the ratio of VOCs to NOx emission reduction much greater than 1 could effectively reduce the local O3 concentration. ⑤ The main sources of atmospheric VOCs in Yinchuan were motor vehicle emission sources （32.3%）, process sources （20.7%）, combustion sources （19.2%）, solvent use sources （12.7%）, gasoline volatile sources （9.1%）, and natural sources （6%）, and the contribution rate of motor vehicle emission sources on polluted days increased by 4.6% compared with that on non-polluted days, indicating that the motor vehicle emission source was an important object of summer VOCs control in Yinchuan.

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BACKGROUND: Clinical research data showed a series of adverse events in the delivery period of primary immune thrombocytopenia (ITP) patients, including high cesarean section rate. Consensus report proposed that for patients with platelet count below 50 × 109/L, prednisone or intravenous immunoglobulins (IVIg) can be given to raise the platelet count in third trimester in preparation for labor. OBJECTIVES: To evaluate the effect of low-dose prednisone or IVIg therapy on delivery outcomes in patients with ITP. STUDY DESIGN: This was a cohort study that included pregnant women with ITP from January 2017 to December 2022. Patients with platelet counts of (20-50) ×109/L at the time of delivery (≥34 weeks) and who had not received any medication before were enrolled in the study. Patients were divided into the pre-delivery medication group (oral prednisone or IVIg) and untreated group according to their preferences. The differences in vaginal delivery rate, postpartum bleeding rate, and platelet transfusion volume between the two groups were compared using t-test, Wilcoxon rank-sum test, and χ2 test. Logistic regression analysis was used to identify the factors affecting vaginal delivery rate and postpartum bleeding rate, and multiple linear regression analysis was used to identify the factors affecting platelet transfusion volume. RESULTS: During the study period, a total of 96 patients with ITP were enrolled, including 70 in the pre-delivery medication group and 26 in the untreated group. The platelet count of pre-delivery medication group was 54.8 ± 34.5 × 109/L, which was significantly higher than that of untreated group 34.4 ± 9.0 × 109/L (p = .004). The vaginal delivery rate of the medication group was higher than the untreated group [60.0% (42/70) vs. 30.8% (8/26), χ2 = 6.49, p = .013]. After adjusting for the proportion of multiparous women and gestational weeks, the results showed that medication therapy during the peripartum period was associated with vaginal delivery (OR = 4.937, 95% CI: 1.511-16.136, p = .008). The postpartum bleeding rates were 22.9% (16/70) and 26.9% (7/26) in the medication group and untreated group, respectively, with no significant difference between the two groups (χ2 = 0.17, p = .789), while the platelet transfusion volume was lower in the medication group than untreated group [(1.1 ± 1.0) vs. (1.6 ± 0.8) U]. CONCLUSION: Pre-delivery medication therapy can increase vaginal delivery rate, reduce platelet transfusion volume, but does not decrease the incidence of postpartum hemorrhage.

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What is the context?The high cesarean section rate has always been a prominent pregnancy issue in ITP patients. The data shows that the reason for cesarean section in most ITP patients may be related to early induced labor due to thrombocytopenia or patients' concerns of bleeding events during delivery. The study of treatment during the perinatal period is expected to further increase platelet count and prepare for safer delivery.What is new?To date, no study has focused on pre-delivery treatment for pregnant ITP patients. In this study, patients with a platelet count<50 × 109/L after 34 weeks can experience a significant increase in platelet count after receiving immunoglobulin or prednisone therapy. The results of this study preliminarily demonstrate IVIg or prednisone is a promising pre-delivery treatment for pregnant ITP patients in preparation for labor. The pre-delivery medication therapy can improve the rate of successful vaginal delivery and reduce the consumption of blood products.What is the impact?This study provides further evidence that the target threshold for platelets should be raised in late third trimester, with a platelet count above 50 × 109/L as the standard for delivery, in order to further reduce the cesarean section rate and blood product infusion in ITP patients.

Asunto(s)

Púrpura Trombocitopénica Idiopática , Humanos , Femenino , Embarazo , Adulto , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Estudios de Cohortes , Parto Obstétrico/métodos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/administración & dosificación , Recuento de Plaquetas

RESUMEN

Protein-based detection methods, enzyme-linked immunosorbent assays (ELISAs) and lateral flow strips, have been widely used for rapid, specific, and sensitive detection of genetically modified organisms (GMOs). However, the traditional ELISA method for the quantitative detection of GMOs has certain limitations. Herein, a quantum dot (QD)-based fluorescence-linked immunosorbent assay was developed using QDs as fluorescent markers for the detection of glyphosate-resistant protein (CP4-EPSPS) in the MON89788 soybean. The end-point fluorescent detection system was carried out using QDs conjugated with a goat anti-rabbit secondary antibody. Compared with the conventional sandwich ELISA method, the newly developed fluorescence-linked immunosorbent assay was highly sensitive and accurate for detecting the CP4-EPSPS protein. The quantified linearity was achieved in the range of 0.05-5% (w/w) for the MON89788 soybean sample. The recovery of protein extracted from mixed MON89788 soybean samples ranged from 87.67% to 116.83%. The limits of detection and limits of quantification were 0.7101 and 2.152 pg/mL, respectively. All of the results indicated that the QD-based fluorescence-linked immunosorbent assay was a highly specific and sensitive method for monitoring the CP4-EPSPS protein in GMOs.

RESUMEN

Objective: This study investigates the association between convalescent plasma therapy and the negative conversion rate in patients with persistent COVID-19 test positivity. Method: A retrospective analysis was conducted on patients with severe or mild to moderate COVID-19 whose viral nucleic acid tests remained positive for over 30 days. Patients were categorized into two groups: those who administered convalescent plasma therapy and those who were not. Data collected included information on therapy strategies used (convalescent plasma, corticosteroids, interferons, etc.), patients' demographic characteristics, comorbidities, therapeutic medications, and nucleic acid testing results. Patients in the convalescent plasma therapy group were matched 1:2 ratio with those in the non-convalescent plasma therapy group. Cumulative negative conversion rates on the fifth, tenth, and fifteenth days post-therapy initiation were analyzed as dependent variables. Independent variables included therapy strategies, demographic characteristics, comorbidities, and therapeutic medication usage. Univariate analysis was conducted, and factors with a p-value (P) less than 0.2 were included in a paired Cox proportional hazards model. Results: There was no statistically significant difference in the cumulative negative conversion rate between the convalescent plasma therapy group and the non-convalescent plasma therapy group on the fifth, tenth, and fifteenth days. Specifically, on day the fifth, the negative conversion rate was 41.46% in the convalescent plasma therapy group compared to 34.15% in the non-convalescent plasma therapy group (HR: 1.72, 95% CI: 0.82-3.61, P = 0.15). On the tenth day, it was 63.41% in the convalescent plasma therapy group and 63.41% in the non-convalescent plasma therapy group (HR: 1.25, 95% CI: 0.69∼2.26, P = 0.46). On the fifteenth day, the negative conversion rate was 85.37% in the convalescent plasma therapy group and 75.61% in the non-convalescent plasma therapy group (HR: 1.19, 95% CI: 0.71-1.97, P = 0.51). Conclusion: Our finding does not support the hypothesis that convalescent plasma therapy could accelerate the time to negative conversion in patients who consistently test positive for COVID-19.

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Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1-/- but not Trpa1-/- mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1-/- mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons.

Asunto(s)

Cadaverina , Ganglios Espinales , Ratones Endogámicos C57BL , Prurito , Canales Catiónicos TRPV , Animales , Prurito/metabolismo , Prurito/inducido químicamente , Canales Catiónicos TRPV/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Masculino , Cadaverina/análogos & derivados , Cadaverina/farmacología , Cadaverina/metabolismo , Ratones , Ratones Noqueados , Humanos , Mastocitos/metabolismo , Mastocitos/efectos de los fármacos , Canal Catiónico TRPA1/metabolismo , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Capsaicina/análogos & derivados

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Indole-based bis-acylhydrazone compounds can inhibit the activity of α-glucosidase and control the concentration of blood glucose. In this paper, the characteristics of three indole-based bis-acylhydrazone compounds with different inhibitory activities of α-glucosidase as well as the interaction with α-glucosidase were studied by experiments and computational simulation techniques. Enzyme kinetic and spectral experiments showed that the indole-based bis-acylhydrazone compounds were able to inhibit enzyme activity through mixed inhibition dominated by competitive inhibition, and during the binding reaction, indole-based bis-acylhydrazone compounds can quench the intrinsic fluorescence of α-glucosidase through static quenching and an aggregation of the indole-based bis-acylhydrazone with α-glucosidase produces a stable complex with a molar ratio of 1:1, and the combination of indole-based bis-acylhydrazone compounds could lead to slight change in the conformation of α-glucosidase. The theoretical simulation demonstrated that the stability of the complex systems was positively correlated with the inhibitory activity of indole-based bis-acylhydrazone compounds, and the indole-based bis-acylhydrazone compounds occupied the active site in the multi-ligand system, resulting in a significant decrease in the binding ability of starch to active amino acids. These results suggested that indole-based bis-acylhydrazone compound was expected to be a new type of α-glucosidase inhibitor.

Asunto(s)

Inhibidores de Glicósido Hidrolasas , Hidrazonas , Indoles , alfa-Glucosidasas , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Indoles/química , Indoles/farmacología , Hidrazonas/química , Hidrazonas/farmacología , Cinética , Simulación del Acoplamiento Molecular , Análisis Espectral

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Alopecia is considered a widespread yet troubling health issue, with limited treatment options. As membranous structures derived from cells carrying proteins, nucleic acids and lipids, exosomes functionally medicate intercellular communication and alter the responses of recipient cells, resulting in disease restraint or promotion. Exosomes have broad prospects in diagnosis and treatment of diseases. Studies using animal models and at the cellular level have clearly shown that exosomes from several types of cells, including dermal papilla cells and mesenchymal stem cells, have a notable capacity to promote hair growth, suggesting that exosomes may provide a new option to treat alopecia. Here, we present a thorough review of the most recent progress in the application of exosomes to hair growth.

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6-Aminocaproic acid (6ACA) and 1,6-hexamethylenediamine (HMDA) are key precursors for nylon synthesis, and both are produced using petroleum-based chemical processes. However, the utilization of bio-based raw materials for biological production of monomers is crucial for nylon industry. In this study, we demonstrated that metabolic engineering of Escherichia coli and selected mutations of α-keto acid decarboxylase successfully synthesized 6ACA and HMDA. An artificial iterative cycle from l-lysine to chain-extended α-ketoacids was introduced into Escherichia coli BL21 (DE3). Then, the extended α-ketoacids were decarboxylated and oxidized for 6ACA production. Overexpression of catalase (KatE) combined with the site-directed mutations of α-isopropylmalate synthase (LeuA) contributed synergistic enhancement effect on synthesis of 6ACA, resulting in a 1.3-fold increase in 6ACA titer. Selected mutations in α-keto acid decarboxylase (KivD) improved its specificity and 170.00 ± 5.57 mg/L of 6ACA with a yield of 0.13 mol/mol (6ACA/ l-lysine hydrochloride) was achieved by shake flask cultivation of the engineered strain with the KivD# (F381Y/V461I). Meanwhile, the engineered E. coli could accumulate 84.67 ± 4.04 mg/L of HMDA with a yield of 0.08 mol/mol (HMDA/ l-lysine hydrochloride) by replacing aldehyde dehydrogenase with bi-aminotransferases. This achievement marks a significant advancement in the biological synthesis of 6-carbon compounds, since the biosynthetic pathways of HMDA are rarely identified.

RESUMEN

Carbonaceous aerosol is an important component of atmospheric fine particulates （PM2.5） that has an important effect on global climate change, atmospheric visibility, regional air quality, and human health. In order to investigate the long-term change characteristics of carbonaceous aerosols under the background of emission reduction, the concentrations of organic carbon （OC）, elemental carbon （EC） in PM2.5 samples, and volatile organic compounds （VOCs） in Chengdu from 2018 to 2021 and the corresponding meteorological factors were obtained through real-time online monitoring. The results showed that the average ρ（OC） and ρ（EC） during the monitoring period were （10.9 ±5.7） µg·m-3 and （2.6 ±1.9） µg·m-3, accounting for 25.2% and 6.0% of PM2.5, respectively, and the average ρ（SOC） was （5.7 ±3.3） µg·m-3, accounting for 52.9% of OC. The concentrations of OC, EC, and PM2.5 showed a downward trend from 2018 to 2020 [PM2.5： The concentration of average annual decrease was -7.1 µg·ï¼ˆm3·a） -1, with an average annual decrease of -14.6 %·a-1； OC： -1.7 µg·ï¼ˆm3·a）-1, -14.2 %·a-1； EC： -0.1 µg·ï¼ˆm3·a）-1, -4.4 %·a-1], and the concentrations of each pollutant in 2021 rebounded in different ranges compared with those in 2020. The concentrations of PM2.5 and OC were as follows： winter > spring > autumn > summer, and the concentrations of EC were as follows： winter > autumn > spring > summer. The proportions of OC and EC were higher in summer and autumn than in other seasons, with the average proportions of 26.8% and 6.9%, respectively. With the aggravation of the pollution level, OC, EC, and SOC concentrations gradually increased, but the proportions in PM2.5 showed a gradual downtrend, indicating that the control factor of PM2.5 pollution in Chengdu was not the carbon component. Source apportionment results showed that carbonaceous aerosols in Chengdu were mainly affected by motor vehicles, industrial sources, biomass combustion sources, and VOCs secondary reaction. From 2019 to 2021, EC was affected by the characteristic components of motor vehicles and decreased yearly. OC and EC were affected by VOCs more in spring and autumn than in other seasons. VOCs emission management should be increased in spring and autumn to reduce the impact of secondary reaction.

RESUMEN

Acute lung injury (ALI) is characterized by an unregulated inflammatory reaction, often leading to severe morbidity and ultimately death. Excessive inflammation caused by M1 macrophage polarization and pyroptosis has been revealed to have a critical role in ALI. Recent study suggests that glycolytic reprogramming is important in the regulation of macrophage polarization and pyroptosis. However, the particular processes underlying ALI have yet to be identified. In this study, we established a Lipopolysaccharide(LPS)-induced ALI model and demonstrated that blocking glycolysis by using 2-Deoxy-D-glucose(2-DG) significantly downregulated the expression of M1 macrophage markers and pyroptosis-related genes, which was consistent with the in vitro results. Furthermore, our research has revealed that Phosphoglycerate Kinase 1(PGK1), an essential enzyme in the glycolysis pathway, interacts with NOD-, LRR- and pyrin domain-containing protein 3(NLRP3). We discovered that LPS stimulation improves the combination of PGK1 and NLRP3 both in vivo and in vitro. Interestingly, the absence of PGK1 reduces the phosphorylation level of NLRP3. Based on in vitro studies with mice bone marrow-derived macrophages (BMDMs), we further confirmed that siPGK1 plays a protective role by inhibiting macrophage pyroptosis and M1 macrophage polarization. The PGK1 inhibitor NG52 suppresses the occurrence of excessive inflammation in ALI. In general, it is plausible to consider a therapeutic strategy that focuses on modulating the relationship between PGK1 and NLRP3 as a means to mitigate the activation of inflammatory macrophages in ALI.

Asunto(s)

Lesión Pulmonar Aguda , Macrófagos , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Fosfoglicerato Quinasa , Piroptosis , Piroptosis/fisiología , Piroptosis/efectos de los fármacos , Animales , Fosfoglicerato Quinasa/metabolismo , Fosfoglicerato Quinasa/genética , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/enzimología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ratones , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Glucólisis/fisiología , Glucólisis/efectos de los fármacos , Masculino , Lipopolisacáridos/toxicidad , Ratones Noqueados , Células Cultivadas

RESUMEN

Electrocatalytic water splitting driven by sustainable energy is a clean and promising water-chemical fuel conversion technology for the production of high-purity green hydrogen. However, the sluggish kinetics of anodic oxygen evolution reaction (OER) pose challenges for large-scale hydrogen production, limiting its efficiency and safety. Recently, the anodic OER has been replaced by a nucleophilic oxidation reaction (NOR) with biomass as the substrate and coupled with a hydrogen evolution reaction (HER), which has attracted great interest. Anode NOR offers faster kinetics, generates high-value products, and reduces energy consumption. By coupling NOR with hydrogen evolution reaction, hydrogen production efficiency can be enhanced while yielding high-value oxidation products or degrading pollutants. Therefore, NOR-coupled HER hydrogen production is another new green electrolytic hydrogen production strategy after electrolytic water hydrogen production, which is of great significance for realizing sustainable energy development and global decarbonization. This review explores the potential of nucleophilic oxidation reactions as an alternative to OER and delves into NOR mechanisms, guiding future research in NOR-coupled hydrogen production. It assesses different NOR-coupled production methods, analyzing reaction pathways and catalyst effects. Furthermore, it evaluates the role of electrolyzers in industrialized NOR-coupled hydrogen production and discusses future prospects and challenges. This comprehensive review aims to advance efficient and economical large-scale hydrogen production.

RESUMEN

Purpose: During the period of COVID-19 pandemic, the social restrictions and isolation exerted a significant impact on the sleep quality of Chinese college students. This study aims to delve into the influence of physical activity on the sleep quality of college students as well as the mediating roles of stress and smartphone addiction. Materials and Methods: A cohort of 274 eligible college students (146 males and 128 females) were selected for the investigation. The International Physical Activity Questionnaire Short Form, Stress Perception Scale, Smartphone Addiction Scale, and Pittsburgh Sleep Quality Index were employed to assess the levels of physical activity, stress, smartphone addiction, and sleep quality among college students. For data analysis, descriptive statistics, correlation analysis, and chained mediation effect tests were performed sequentially. Results: The findings revealed: (1) a significant negative correlation between physical activity and stress, smartphone addiction, and sleep quality among college students (r = -0.216, p < 0.001; r = -0.224, p < 0.001; r = -0.259, p < 0.001); (2) independent mediating roles of stress and smartphone addiction in the relationship between physical activity and sleep quality; and (3) chained mediating effects of stress and smartphone addiction in the association between physical activity and sleep quality. Conclusion: This study deepens our comprehension of how physical activity augments the quality of slumber, concurrently emphasizing that mitigating stress levels and alleviating smartphone addiction constitute effective strategies for preventing sleep issues among college students.