RESUMO
The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.
Assuntos
Apolipoproteína L1/genética , População Negra/genética , COVID-19/genética , Predisposição Genética para Doença/genética , Sepse/genética , Animais , Apolipoproteína L1/sangue , População Negra/estatística & dados numéricos , COVID-19/patologia , DNA Mitocondrial/metabolismo , Células Endoteliais/metabolismo , Humanos , Inflamação/genética , Inflamação/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Mitofagia/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fatores de Risco , Sepse/patologia , Índice de Gravidade de Doença , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
Dinitroimidazole (DNI) and dinitropyrazole (DNP), along with their congeners, possess similar molecular structures but exhibit distinct melting points. To analyse and elucidate the fundamental reasons for property differences from the perspective of intermolecular interactions, we proposed a simplified approach named binding energy in clusters (BEC) in computing weak interactions within complex crystal systems. Based on the results of the symmetry-adapted perturbation theory (SAPT) calculations, an approximate estimation of the melting point range can be derived by taking into account the cumulative effect (energy of electrostatic, dispersion and induction terms) and repulsive effect (energy of exchange term) values. We have also proposed a formula for calculating the specific melting point, which indicates that stronger intermolecular interactions have a major impact on the melting point, while the distribution of weak interactions also affects the melting point. This work would provide an effective reference for molecular design and structure-performance analysis.
RESUMO
Background: Preexisting cardiovascular disease (CVD) and hypertension are each associated with poor prognosis in peritoneal dialysis (PD) patients. Joint associations of preexisting CVD and hypertension have not been comprehensively evaluated in this population. Methods: We conducted a retrospective cohort study of 3073 Chinese incident PD patients from five dialysis centres between January 1, 2005, and December 31, 2018. The joint associations between preexisting CVD, hypertension, and mortality were analysed using Cox regression models. Results: Over a median of 33.7 months of follow-up, 581 (18.6%) patients died, with 286 (9.3%) deaths due to CVD. After adjusting for confounding factors, the preexisting CVD coexisting with hypertension, preexisting CVD, and hypertension groups had higher risks of all-cause mortality (hazard ratio [HR]: 3.97, 95% confidence interval [CI]: 3.06 to 5.15; HR: 2.21, 95% CI: 1.29 to 3.79; and HR: 1.83, 95% CI: 1.47 to 2.29, respectively) and CVD mortality (HR: 4.68, 95% CI: 3.27 to 6.69; HR: 2.10, 95% CI: 0.95 to 4.62; and HR: 1.86, 95% CI: 1.36 to 2.54, respectively) than the control group without preexisting CVD or hypertension (p for trend < 0.001). There was no interaction between subgroup analyses (p > 0.05). The joint associations showed similar patterns using the Fine-Gray competing risk models. Conclusions: Preexisting CVD and hypertension at the start of PD were additive prognostic utilities for mortality, and preexisting CVD was more strongly associated with mortality than hypertension.
RESUMO
Melting point prediction for organic molecules has drawn widespread attention from both academic and industrial communities. In this work, a learnable graph neural fingerprint (GNF) was employed to develop a melting point prediction model using a dataset of over 90,000 organic molecules. The GNF model exhibited a significant advantage, with a mean absolute error (MAE) of 25.0 K, when compared to other featurization methods. Furthermore, by integrating prior knowledge through a customized descriptor set (i.e., CDS) into GNF, the accuracy of the resulting model, GNF_CDS, improved to 24.7 K, surpassing the performance of previously reported models for a wide range of structurally diverse organic compounds. Moreover, the generalizability of the GNF_CDS model was significantly improved with a decreased MAE of 17 K for an independent dataset containing melt-castable energetic molecules. This work clearly demonstrates that prior knowledge is still beneficial for modeling molecular properties despite the powerful learning capability of graph neural networks, especially in specific fields where chemical data are lacking.
RESUMO
Coding variants (named G1 and G2) in Apolipoprotein L1 (APOL1) can explain most excess risk of kidney disease observed in African American individuals. It has been proposed that risk variant APOL1 dose, such as increased risk variant APOL1 level serves as a trigger (second hit) for disease development. The goal of this study was to determine whether lowering risk variant APOL1 levels protects from disease development in a podocyte-specific transgenic mouse disease model. We administered antisense oligonucleotides (ASO) targeting APOL1 to podocyte-specific G2APOL1 mice and observed efficient reduction of APOL1 levels. APOL1 ASO1, which more efficiently lowered APOL1 transcript levels, protected mice from albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and renal failure. Administration of APOL1 ASO1 was effective even for established disease in the NEFTA-rtTA/TRE-G2APOL1 (NEFTA/G2APOL1) mice. We observed a strong correlation between APOL1 transcript level and disease severity. We concluded that APOL1 ASO1 may be an effective therapeutic approach for APOL1-associated glomerular disease.
Assuntos
Nefropatias , Podócitos , Insuficiência Renal , Animais , Apolipoproteína L1/genética , Apolipoproteínas/genética , Variação Genética , Nefropatias/genética , Nefropatias/terapia , Camundongos , Camundongos Transgênicos , Oligonucleotídeos Antissenso/genéticaRESUMO
BACKGROUND: Total cholesterol is inversely associated with mortality in dialysis patients, which seems implausible in real-world clinical practice. May there be an optimal range of total cholesterol associated with a lower mortality risk? We aimed to evaluate the optimal range for peritoneal dialysis (PD) patients. METHODS: We conducted a retrospective real-world cohort study of 3565 incident PD patients from five PD centers between January 1, 2005, and May 31, 2020. Baseline variables were collected within one week before the start of PD. The associations between total cholesterol and mortality were examined using cause-specific hazard models. RESULTS: 820 (23.0%) patients died, including 415 cardiovascular deaths, during the follow-up period. Restricted spline plots showed a U-curved association of total cholesterol with mortality. Compared with the reference range (4.10-4.50 mmol/L), high levels of total cholesterol (> 4.50 mmol/L) were associated with increased risks of all-cause (hazard ratio [HR] 1.35, 95% confidence index [CI] 1.08-1.67) and cardiovascular mortality (HR 1.38, 95% CI 1.09-1.87). Similarly, compared with the reference range, low levels of total cholesterol (< 4.10mmol/L) were also associated with high risks of all-cause (HR 1.62, 95% CI 1.31-1.95) and cardiovascular mortality (HR 1.72, 95% CI 1.27-2.34). CONCLUSION: Total cholesterol levels at the start of PD between 4.10 and 4.50 mmol/L (158.5 to 174.0 mg/dL), an optimal range, were associated with lower risks of death than higher or lower levels, resulting in a U-shaped association.
Assuntos
Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Diálise Renal , Estudos Retrospectivos , Estudos de Coortes , ColesterolRESUMO
BACKGROUND: New lipid-lowering therapy at the start of dialysis and measurement of lipid parameters over the follow-up period is not recommended in dialysis patients, which seems unappropriated in clinical practice. We aimed to examine the effect of hyperlipidemia on mortality in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: A retrospective cohort study was performed, including 2939 incident CAPD patients from five dialysis facilities between January 1, 2005, and December 31, 2018. The primary outcome was all-cause mortality. The association between hyperlipidemia at the start of CAPD and all-cause mortality was evaluated using Cox proportional hazards regression. RESULTS: Of 2939 with a median age of 50.0 (interquartile range, 39.0-61.0), 1697 (57.7%) were men, 533 (18.1%) had hyperlipidemia, 549 (18.7%) had diabetes mellitus, 1915 (65.2%) had hypertension, and 410 (14.0%) had a history of CVD. During the median follow-up period of 35.1 months, 519 (17.7%) died, including 402 (16.7%, 47.4/1000 patient-years) in the non-hyperlipidemia group and 117 (22.0%, 71.1/1000 patient-years) in the hyperlipidemia group. Over the overall follow-up period, patients with hyperlipidemia had an equally high risk of all-cause mortality throughout follow-up as those without hyperlipidemia ([HR] 1.04, 95% confidence interval [CI] 0.83 to 1.31). However, from the 48-month follow-up onwards, hyperlipidemia was associated with a 2.26 (95% CI 1.49 to 3.43)-time higher risk of all-cause mortality than non-hyperlipidemia. Hypertension modified the association between hyperlipidemia and all-cause mortality (P for interaction < 0.001). A significantly increased risk of all-cause mortality was observed among patients with hypertension (HR 2.27, 95%CI 1.44-3.58). CONCLUSION: Among CAPD patients, hyperlipidemia at the beginning of CAPD was associated with a high risk of long-term mortality. Hypertension may mediate the association. Our findings suggested that long-term lipid-lowering treatment should be used in those patients with hyperlipidemia.
Assuntos
Hiperlipidemias , Hipertensão , Falência Renal Crônica , Diálise Peritoneal , Masculino , Humanos , Feminino , Estudos Retrospectivos , Diálise Renal , Diálise Peritoneal/efeitos adversos , Hiperlipidemias/epidemiologia , Hipertensão/epidemiologia , Lipídeos , Modelos de Riscos Proporcionais , Falência Renal Crônica/terapiaRESUMO
BACKGROUND AND AIMS: Although hyperuricemia is associated with congestive heart failure (CHF), hyperuricemic patients frequently have other comorbidities. Thus, it is difficult to distinguish the role of hyperuricemia from that of other comorbid conditions in CHF. The aim of this study was to evaluate the association between hyperuricemia and CHF in elderly patients without comorbidities. METHODS AND RESULTS: Subjects aged ≥65 years were analyzed at enrollment (2009-2012) and during the 4-year follow-up period at the Kangjian Community Health Center of Shanghai. Subjects were excluded if they had hypertension, diabetes mellitus, preexisting cardiovascular disease, hyperlipidemia, overweight or obesity, a history of gout or hyperuricemia and were taking medication for their condition, or chronic kidney disease. The primary outcome of this study was to investigate the impact of asymptomatic hyperuricemia on incident CHF. We used Cox regression to estimate the hazard ratio (HR) for incident CHF events between hyperuricemic (defined as an SUA level >7 mg/dL in men and ≥6 mg/dL in women) and normouricemic subjects. A total of 2749 subjects (70.9 ± 6.0 years) were followed for 47.4 ± 3.6 months. Asymptomatic hyperuricemia was associated with an increased cumulative incidence of incident CHF events (6.5% versus 3.1%, odds ratio [OR] = 2.15, 95% confidence index [CI]: 1.39-3.33, p = 0.001). After adjusting for confounding factors, including baseline eGFR, hyperuricemia independently predicted the risk of incident CHF events (HR = 2.34, 95% CI: 1.50-3.63, p < 0.001). CONCLUSION: Asymptomatic hyperuricemia was a valuable biomarker for predicting the development of incident CHF in elderly patients without comorbidities.
Assuntos
Insuficiência Cardíaca/epidemiologia , Hiperuricemia/epidemiologia , Ácido Úrico/sangue , Fatores Etários , Idoso , Doenças Assintomáticas , Biomarcadores/sangue , China/epidemiologia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Incidência , Estudos Longitudinais , Masculino , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
OBJECTIVE: Glutamate is an excitatory neurotransmitter in the central nervous system that participates in initiation and maintenance of sleep and wakefulness. The mechanisms involved occur in the brainstem, lateral hypothalamus, and basal forebrain. Our previous study suggested that higher levels of glutamate in cerebrospinal fluid (CSF) contributed to poorer sleep quality. Smoking has been shown to be harmful to sleep quality. In the present study, we recruited non-smokers and heavy smokers and measured the concentration of CSF glutamate in order to investigate the associations among smoking status, sleep quality, and CSF glutamate levels. METHODS: We recruited 147 men (n = 68 non-smokers, 30.31 ± 9.10 years; n = 79 heavy smokers, 34.54 ± 10.71 years). Glutamate concentrations in CSF were measured by spectrophotometry, and subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: PSQI total scores were significantly higher in heavy smokers than that in non-smokers (p < 0.001). Glutamate concentrations in CSF were lower in heavy smokers than that in non-smokers (p < 0.001). CSF glutamate levels positively correlated with PSQI total scores in the non-smokers group (r = 0.313, p = 0.011, effect size = 0.324). No correlation was found between CSF glutamate levels and PSQI total scores in the heavy smokers group (p > 0.05). Multivariable linear regression analysis showed that years of smoking was contributed to the PSQI total scores (p = 0.008), and cigarettes smoked per day contributed to the decreased CSF glutamate levels in heavy smokers (p = 0.001). CONCLUSION: Poorer subjective sleep quality and lower CSF glutamate concentrations were observed in the heavy smokers group than in the non-smokers group. In addition, lack of correlation was observed between CSF glutamate levels and PSQI scores in the heavy smokers.
Assuntos
Ácido Glutâmico/líquido cefalorraquidiano , Transtornos do Sono-Vigília/líquido cefalorraquidiano , Fumar/líquido cefalorraquidiano , Tabagismo/líquido cefalorraquidiano , Adulto , Correlação de Dados , Humanos , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
BACKGROUND: MicroRNAs (miRNAs) are stable in circulation, and their unique expression profiles can serve as fingerprints for various diseases. This study explored whether plasma miRNAs could be used as biomarkers to evaluate disease activity in patients with focal segmental glomerulosclerosis (FSGS). STUDY DESIGN: Retrospective and prospective cohorts. SETTING & PARTICIPANTS: 78 patients with FSGS with nephrotic proteinuria (protein excretion > 3.5g/24 h), 35 patients with FSGS in complete remission, 63 patients with membranous nephropathy, 59 patients with diabetic nephropathy, and 69 apparently healthy controls were recruited. Plasma samples from 51 other patients with FSGS with nephrotic proteinuria were collected prospectively before and after steroid treatment. PREDICTORS: Plasma miRNA concentration. OUTCOMES: Complete remission (protein excretion < 0.4g/24 h), or no response (sustained protein excretion > 3.5g/24 h after 8 weeks of steroid treatment). MEASUREMENTS: Quantitative reverse transcription-polymerase chain reaction analysis of plasma miRNAs. RESULTS: Increases in miR-125b, miR-186, and miR-193a-3p levels were identified in a pooled plasma sample of 9 patients with FSGS compared with that of 9 healthy controls and were confirmed with individual samples from patients with FSGS (n=32) and healthy controls (n=30). Areas under the receiver operating characteristic curves of miR-125b, miR-186, miR-193a-3p, and the 3 miRNAs in combination were 0.882, 0.789, 0.910, and 0.963, respectively. miR-125b and miR-186 concentrations were significantly lower in patients with FSGS in complete remission (n=35) than those with nephrotic proteinuria (n=37). In a prospective study, miR-125b and miR-186 levels declined markedly in patients with FSGS with complete remission (n=29), but not those with no response (n=22), after steroid treatment. Plasma miR-125b and miR-186 levels were not elevated in patients with membranous nephropathy (n=63) and diabetic nephropathy (n=59) regardless of degree of proteinuria. Last, plasma miR-186, but not miR-125b, level was correlated with degree of proteinuria in patients with FSGS (151 samples). LIMITATIONS: Relatively small cohort size. CONCLUSIONS: Plasma miR-186 may be a biomarker for FSGS with nephrotic proteinuria.
Assuntos
Glomerulosclerose Segmentar e Focal/sangue , Glomerulosclerose Segmentar e Focal/diagnóstico , MicroRNAs/sangue , Proteinúria/sangue , Proteinúria/diagnóstico , Adulto , Biomarcadores/sangue , Estudos de Coortes , Feminino , Glomerulosclerose Segmentar e Focal/epidemiologia , Humanos , Masculino , Estudos Prospectivos , Proteinúria/epidemiologia , Estudos Retrospectivos , Adulto JovemRESUMO
The progression of podocytopathies is quite variable among patients and the underlying reason for this remains unclear. Here, we report that autophagic activity in podocytes plays a critical role in controlling the progression of podocytopathies. Morphological and biochemical studies on renal biopsies from patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) showed that glomeruli, and in particular podocytes, from MCD patients had higher levels of Beclin1-mediated autophagic activity than glomeruli from FSGS patients. Repeat renal biopsies of MCD patients enabled tracking of podocyte autophagic activity and confirmed that patients maintaining high podocyte autophagic activity retained MCD status, whereas patients with decreased podocyte autophagic activity progressed to FSGS. Inhibition of autophagic activity, by knocking down Beclin1 or by treating with 3-methyladenine (3-MA) or chloroquine, enhanced puromycin aminonucleoside (PAN)-induced apoptosis of podocytes. In contrast, rapamycin-mediated promotion of autophagic activity decreased this apoptosis. In PAN-treated rats, inhibition of autophagy with 3-MA or chloroquine resulted in earlier onset and greater proteinuria, more extensive foot-process effacement, and reduction in podocyte markers, whereas rapamycin-mediated stimulation of autophagy led to decreased proteinuria and less severe foot-process effacement, but higher expression of podocyte markers. This study demonstrates that podocyte autophagic activity plays a critical protective role in renal injury and that maintaining podocyte autophagic activity represents a potential therapeutic strategy for controlling the progression of podocytopathies.
Assuntos
Injúria Renal Aguda/metabolismo , Autofagia/fisiologia , Glomerulosclerose Segmentar e Focal/metabolismo , Podócitos/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/fisiopatologia , Humanos , Masculino , Podócitos/efeitos dos fármacos , Proteinúria/metabolismo , Puromicina Aminonucleosídeo/farmacologia , Ratos WistarRESUMO
MicroRNAs (miRNAs) are essential for podocyte homeostasis, and the miR-30 family may be responsible for this action. However, the exact roles and clinical relevance of miR-30s remain unknown. In this study, we examined the expression of the miR-30 family in the podocytes of patients with FSGS and found that all members are downregulated. Treating cultured human podocytes with TGF-ß, LPS, or puromycin aminonucleoside (PAN) also downregulated the miR-30 family. Podocyte cytoskeletal damage and apoptosis caused by treatment with TGF-ß or PAN were ameliorated by exogenous miR-30 expression and aggravated by miR-30 knockdown. Moreover, we found that miR-30s exert their protective roles by direct inhibition of Notch1 and p53, which mediate podocyte injury. In rats, treatment with PAN substantially downregulated podocyte miR-30s and induced proteinuria and podocyte injury; however, transfer of exogenous miR-30a to podocytes of PAN-treated rats ameliorated proteinuria and podocyte injury and reduced Notch1 activation. Finally, we demonstrated that glucocorticoid treatment maintains miR-30 expression in cultured podocytes treated with TGF-ß, LPS, or PAN and in the podocytes of PAN-treated rats. Glucocorticoid-sustained miR-30 expression associated with reduced Notch1 activation and alleviated podocyte damage. Taken together, these findings demonstrate that miR-30s protect podocytes by targeting Notch1 and p53 and that the loss of miR-30s facilitates podocyte injury. In addition, sustained miR-30 expression may be a novel mechanism underlying the therapeutic effectiveness of glucocorticoids in treating podocytopathy.
Assuntos
MicroRNAs/genética , Podócitos/metabolismo , Animais , Células Cultivadas , Dexametasona/farmacologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Glucocorticoides/farmacologia , Humanos , Lipopolissacarídeos/farmacologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/patologia , Puromicina Aminonucleosídeo/farmacologia , Ratos , Ratos Wistar , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genéticaRESUMO
The lack of understanding of the mechanism of renal injury in IgA nephropathy (IgAN) hinders the development of personalized treatment plans and targeted therapies. Improved insight into the cause of renal dysfunction in IgAN is necessary to enhance the effectiveness of strategies for slowing the progression of the disease. This study examined single cell RNA sequencing (scRNA seq) and bulk-RNA seq data and found that the gene expression of renal intrinsic cells (RIC) was significantly changed in patients with renal impairment, with a primary focus on energy metabolism. We discovered a clear metabolic reprogramming of RIC during renal function impairment (RF) using the 'scMetabolism' package, which manifested as a weakening of oxidative phosphorylation, alterations in fatty acid metabolism, and changes in glycolysis. Cellular communication analysis revealed that communication between macrophages (Ma) and RIC became more active and impacted cell function through the ligand-receptor-transcription factor (L-R-TF) axis in patients with RF. Our studies showed a notable upsurge in the expression of gene CLU and the infiltration of CLU+ Ma in patients with RF. CLU is a multifunctional protein, extensively involved in processes such as cell apoptosis and immune responses. Data obtained from the Nephroseq V5 database and multiplex immunohistochemistry (mIHC) were used to validate the findings, which were found to be robustly correlated with estimated glomerular filtration rate (eGFR) of the IgAN patients, as demonstrated by linear regression (LR). This study provides new insights into the cellular and molecular changes that occur in IgAN during renal impairment, revealing that elevated expression of CLU and CLU+ Ma percolation are common features in patients with RF. These findings offer potential targets and strategies for personalized management and targeted therapy of IgAN.
RESUMO
Schizophrenia has been linked to cognitive impairment and white matter damage in a growing number of studies this year. In this study, we used the MK-801-induced schizophrenia-like mice model to investigate the effects of quetiapine on behavioral changes and myelin loss in the model mice. The subjects selected for this study were C57B6/J male mice, MK-801 (1 mg/kg/d intraperitoneal injection) modeling for 1 week and quetiapine (10 mg/kg/d intraperitoneal injection) treatment for 2 weeks. Behavioral tests were then performed using the three-chamber paradigm test and the Y maze test. Moreover, western blot, immunohistochemistry, and immunofluorescence were conducted to investigate the changes in oligodendrocyte spectrum markers. In addition, we performed some mechanism-related proteins by western blot. Quetiapine ameliorated cognitive impairment and cerebral white matter damage in MK-801 model mice, and the mechanism may be related to the PI3K/AKT pathways. The present study suggests that quetiapine has a possible mechanism for treating cognitive impairment and white matter damage caused by schizophrenia.
Assuntos
Disfunção Cognitiva , Esquizofrenia , Substância Branca , Humanos , Masculino , Camundongos , Animais , Fumarato de Quetiapina/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Maleato de Dizocilpina/efeitos adversos , Substância Branca/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Disfunção Cognitiva/tratamento farmacológicoRESUMO
Objectives: Repetitive transcranial magnetic stimulation (rTMS) has been considered as an effective antidepressant treatment; however, the mechanism of its antidepressant effect is still unclear. Fluoxetine, a selective serotonin reuptake inhibitor antidepressant, may be neuroprotective. The objective of the present study was to evaluate the effect and underlying possible neuroprotective mechanism of rTMS and fluoxetine on abnormal behaviours in a depressive mouse model induced by chronic unpredictable mild stress (CUMS).Methods: After 28 days of CUMS exposure, mice were chronically treated with rTMS (10 Hz for 5 s per train, total 20 trains per day) and (or) fluoxetine (5 mg/kg/day, intraperitoneally) for 28 days targeting on the frontal cortex. After the behavioural tests, the protein expressions of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) were measured by immunohistochemistry and (or) Western Blot.Results: The results showed rTMS and (or) fluoxetine attenuated the locomotion decrease, anxiety and depressive like behaviours in the CUMS-exposed mice.Conclusion: Our results suggest that both rTMS and fluoxetine could benefit the CUMS-induced abnormal behaviours including depressive-like behaviours, and the beneficial effects of rTMS as well as fluoxetine on depression might be partly related to their neuroprotective effect on attenuating astroglial activation and BDNF decrease.
Assuntos
Depressão , Fluoxetina , Camundongos , Animais , Fluoxetina/farmacologia , Fluoxetina/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulação Magnética Transcraniana , Antidepressivos/farmacologia , Modelos Animais de Doenças , Estresse Psicológico/terapia , Estresse Psicológico/metabolismo , HipocampoRESUMO
Sirolimus (SRL) is commonly used in transplant patients to prevent organ transplant rejection. The current guidelines recommend to perform SRL therapeutic drug monitoring regularly to improve treatment outcomes and avoid adverse effects. Consequently, a precise and accurate method for determining SRL is crucial in clinical practice. Currently, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassays have been widely adopted for determining SRL concentrations. However, previous studies have shown that immunoassays exhibit a positive bias compared to LC-MS/MS. As the new updated version of the EMIT-based Viva-E® System (SVPS), this study aims to compare SRL blood concentrations measured by the SVPS and LC-MS/MS. The residual whole-blood samples obtained from transplant patients were simultaneously analyzed using the SVPS and LC-MS/MS, respectively. The correlation between the two assays was analyzed using the linear regression analysis and Deming linear regression. The Pearson correlation coefficient and Intraclass correlation coefficient (ICC) analysis were executed. The Paired Wilcoxon test and Bland-Altman analysis were performed to assess the concordance between the two methods. The SVPS considerably increased SRL concentration value by 46.62â¯% as compared to the LC-MS/MS method. When SRL concentrations measured by the SVPS were above 4.0â¯ng/mL, there was no significant difference between the corrected SVPS concentrations after using the Deming linear regression equation, indicating their interchangeability. Given the significant disparities observed between EMIT and LC-MS/MS, it is crucial to indicate the methodology and instruments in both TDM reports and future clinical guidelines. Our study also provides the conversion formulas between the SVPS and LC-MS/MS, which can be applied as a reference for different clinical centers.
Assuntos
Monitoramento de Medicamentos , Imunossupressores , Sirolimo , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Sirolimo/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Imunossupressores/sangue , Imunoensaio/métodos , Masculino , Feminino , Reprodutibilidade dos Testes , Povo Asiático , China , Pessoa de Meia-Idade , Adulto , Transplante de Órgãos/métodos , População do Leste Asiático , Espectrometria de Massa com Cromatografia LíquidaRESUMO
Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.
Assuntos
Hipertensão , Nefropatias , Ratos , Humanos , Animais , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Cromatina/genética , Amilorida/farmacologia , Mineralocorticoides/farmacologia , Rim , Nefropatias/genética , Perfilação da Expressão GênicaRESUMO
In the case of a large bone defect, the human endogenous electrical field is no longer sufficient. Therefore, it is necessary to support structural electrical bone scaffolds. Barium titanate (BT) has received much attention in bone tissue engineering applications due to its biocompatibility and ability to maintain charged surfaces. However, its processability is poor and it does not have the biological activity to promote mineralization, which limits its use in bone repair. In this paper, a composite bone scaffold with excellent piezoelectric properties was prepared by combining 20 wt% calcium silicate. The influence of the light curing process on the properties of the piezoelectric biological scaffold was investigated by comparing it with the traditional piezoelectric ceramic molding method (dry pressing). Despite the structural features of 3D printing (layered structure, pore features), the piezoelectric and mechanical properties of the scaffold are weakened. However, 3D-printed scaffolds can combine structural and piezoelectric properties, which makes the 3D-printed scaffold more effective in terms of degradation and antibacterial performance. In terms of cell activity, piezoelectric properties attract proteins and nutrients into the scaffold, promoting cell growth and differentiation. Besides, it is undeniable that the pore structure of the scaffolds plays an important role in the biological properties. Finally, the 3D printed scaffolds have excellent antimicrobial properties due to the redox reaction under piezoelectric effect as well as structural characterization.
Assuntos
Antibacterianos , Artrodese , Compostos de Cálcio , Silicatos , Humanos , Bário , Impressão TridimensionalRESUMO
High-density localization based on deep learning is a very effective method to accelerate single molecule localization microscopy (SMLM). Compared with traditional high-density localization methods, deep learning-based methods enable a faster data processing speed and a higher localization accuracy. However, the reported high-density localization methods based on deep learning are still not fast enough to enable real time data processing for large batches of raw images, which is probably due to the heavy computational burden and computation complexity in the U-shape architecture used in these models. Here we propose a high-density localization method called FID-STORM, which is based on an improved residual deconvolutional network for the real-time processing of raw images. In FID-STORM, we use a residual network to extract the features directly from low-resolution raw images rather than the U-shape network from interpolated images. We also use a model fusion from TensorRT to further accelerate the inference of the model. In addition, we process the sum of the localization images directly on GPU to obtain an additional speed gain. Using simulated and experimental data, we verified that the FID-STORM method achieves a processing speed of 7.31â ms/frame at 256 × 256 pixels @ Nvidia RTX 2080 Ti graphic card, which is shorter than the typical exposure time of 10â¼30â ms, thus enabling real-time data processing in high-density SMLM. Moreover, compared with a popular interpolated image-based method called Deep-STORM, FID-STORM enables a speed gain of â¼26 times, without loss of reconstruction accuracy. We also provided an ImageJ plugin for our new method.
RESUMO
Background: Alzheimer's disease (AD) is characterized by the presence of gray matter lesions and alterations in white matter. This study aims to investigate the research related to white matter in the context of AD from a Bibliometric standpoint. Methods: Regular and review articles focusing on the research pertaining to Alzheimer's disease (AD) and white matter were extracted from the Web of Science Core Collection (WOSCC) database, covering the period from its inception to 10th July 2023. The "Bibliometrix" R package was employed to summarize key findings, to quantify the occurrence of top keywords, and to visualize the collaborative network among countries. Furthermore, VOSviewer software was utilized to conduct co-authorship and co-occurrence analyses. CiteSpace was employed to identify the most influential references and keywords based on their citation bursts. The retrieval of AD- and white matter-related publications was conducted by the Web of Science Core Collection. Bibliometric analysis and visualization, including the examination of annual publication distribution, prominent countries, active institutions and authors, core journals, co-cited references, and keywords, were carried out by using VOSviewer, CiteSpace, the Bibliometrix Package, and the ggplot2 Package. The quality and impact of publications were assessed using the total global citation score and total local citation score. Results: A total of 5,714 publications addressing the intersection of Alzheimer's disease (AD) and white matter were included in the analysis. The majority of publications originated from the United States, China, and the United Kingdom. Prominent journals were heavily featured in the publication output. In addition to "Alzheimer's disease" and "white matter," "mild cognitive impairment," "MRI" and "atrophy" had been frequently utilized as "keywords." Conclusion: This Bibliometric investigation delineated a foundational knowledge framework that encompasses countries, institutions, authors, journals, and articles within the AD and white matter research domain spanning from 1981 to 2023. The outcomes provide a comprehensive perspective on the broader landscape of this research field.