RESUMO
The anterior cingulate cortex (ACC) and visual cortex are integral components of the neurophysiological mechanisms underlying migraine, yet the impact of altered connectivity patterns between these regions on migraine treatment remains unknown. To elucidate this issue, we investigated the abnormal causal connectivity between the ACC and visual cortex in patients with migraine without aura (MwoA), based on the resting-state functional magnetic resonance imaging data, and its predictive ability for the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs). The results revealed increased causal connectivity from the bilateral ACC to the lingual gyrus (LG) and decreased connectivity in the opposite direction in nonresponders compared with the responders. Moreover, compared with the healthy controls, nonresponders exhibited heightened causal connectivity from the ACC to the LG, right inferior occipital gyrus (IOG) and left superior occipital gyrus, while connectivity patterns from the LG and right IOG to the ACC were diminished. Based on the observed abnormal connectivity patterns, the support vector machine (SVM) models showed that the area under the receiver operator characteristic curves for the ACC to LG, LG to ACC and bidirectional models were 0.857, 0.898, and 0.939, respectively. These findings indicate that neuroimaging markers of abnormal causal connectivity in the ACC-visual cortex circuit may facilitate clinical decision-making regarding NSAIDs administration for migraine management.
Assuntos
Enxaqueca sem Aura , Córtex Visual , Humanos , Giro do Cíngulo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Enxaqueca sem Aura/patologia , Córtex Visual/diagnóstico por imagem , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios , EncéfaloRESUMO
3D CsPbX3 inorganic perovskite materials have attracted much attention in optoelectronic devices because of their strong absorbance, high photoluminescent quantum yield, tunable band gap, and narrow emission bandwidth. However, their practical usefulness is limited due to their poor stability in ambient conditions. Here, we created photoluminescent 0D Cs4PbX6 (X = Br, Br/I) suspensions in toluene by adding a small amount of water. The photoluminescent 0D Cs4PbX6 perovskite was mixed with polymethylmethacrylate (PMMA) forming 0D Cs4PbX6/PMMA composite films with higher PL, stability, transparency, and transmittance than that of the 3D CsPbX3/PMMA composite films prepared separately. Moreover, the PL intensity maintains 90% of the initial value after 30 days in water, showing excellent water stability. The flexible white-light LED device prepared by the composite films illustrated good luminescence performance with color rendering index 74.77, chromaticity coordinates (0.32, 0.33), and color temperature 6997 K.
RESUMO
BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are considered first-line medications for acute migraine attacks. However, the response exhibits considerable variability among individuals. Thus, this study aimed to explore a machine learning model based on the percentage of amplitude oscillations (PerAF) and gray matter volume (GMV) to predict the response to NSAIDs in migraine treatment. METHODS: Propensity score matching was adopted to match patients having migraine with response and nonresponse to NSAIDs, ensuring consistency in clinical characteristics and migraine-related features. Multimodal magnetic resonance imaging was employed to extract PerAF and GMV, followed by feature selection using the least absolute shrinkage and selection operator regression and recursive feature elimination algorithms. Multiple predictive models were constructed and the final model with the smallest predictive residuals was chosen. The model performance was evaluated using the area under the receiver operating characteristic (ROCAUC) curve, area under the precision-recall curve (PRAUC), balance accuracy (BACC), sensitivity, F1 score, positive predictive value (PPV), and negative predictive value (NPV). External validation was performed using a public database. Then, correlation analysis was performed between the neuroimaging predictors and clinical features in migraine. RESULTS: One hundred eighteen patients with migraine (59 responders and 59 non-responders) were enrolled. Six features (PerAF of left insula and left transverse temporal gyrus; and GMV of right superior frontal gyrus, left postcentral gyrus, right postcentral gyrus, and left precuneus) were observed. The random forest model with the lowest predictive residuals was selected and model metrics (ROCAUC, PRAUC, BACC, sensitivity, F1 score, PPV, and NPV) in the training and testing groups were 0.982, 0.983, 0.927, 0.976, 0.930, 0.889, and 0.973; and 0.711, 0.648, 0.639, 0.667,0.649, 0.632, and 0.647, respectively. The model metrics of external validation were 0.631, 0.651, 0.611, 0.808, 0.656, 0.553, and 0.706. Additionally, a significant positive correlation was found between the GMV of the left precuneus and attack time in non-responders. CONCLUSIONS: Our findings suggest the potential of multimodal neuroimaging features in predicting the efficacy of NSAIDs in migraine treatment and provide novel insights into the neural mechanisms underlying migraine and its optimized treatment strategy.
Assuntos
Anti-Inflamatórios não Esteroides , Substância Cinzenta , Imageamento por Ressonância Magnética , Transtornos de Enxaqueca , Neuroimagem , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/diagnóstico por imagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Adulto , Masculino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/patologia , Neuroimagem/métodos , Aprendizado de Máquina , Pessoa de Meia-Idade , BiomarcadoresRESUMO
To understand the genome-wide information of the GRF family genes in broomcorn millet and their expression profile in the vegetative meristems, bioinformatic methods and transcriptome sequencing were used to analyze the characteristics, physical and chemical properties, phylogenetic relationship, chromosome distribution, gene structure, cis-acting elements and expression profile in stem meristem for the GRF family members. The results showed that the GRF gene family of millet contains 21 members, and the PmGRF gene is unevenly distributed on 12 chromosomes. The lengths of PmGRF proteins vary from 224 to 618 amino acids, and the isoelectric points are between 4.93-9.69. Each member of the family has 1-4 introns and 2-5 exons. The protein PmGRF13 is localized in both the nucleus and chloroplast, and the rest PmGRF proteins are located in the nucleus. Phylogenetic analysis showed that the 21 GRF genes were divided into 4 subfamilies (A,B,C and D) in broomcorn millet. The analysis of cis-acting elements showed that there were many cis-acting elements involved in light response, hormone response, drought induction, low temperature response and other environmental stress responses in the 2000 bp sequence upstream of the GRF genes. Transcriptome sequencing and qRT-PCR analyses showed that the expression levels of PmGRF3 and PmGRF12 in the dwarf variety Zhang778 were significantly higher than those of the tall variety Longmi12 in the internode and node meristems at the jointing stage, while the expression patterns of PmGRF4, PmGRF16 and PmGRF21 were reverse. In addition, the expression levels of PmGRF2 and PmGRF5 in the internode of Zhang778 were significantly higher than Longmi12. The other GRF genes were not or insignificantly expressed. These results indicated that seven genes, PmGRF2, PmGRF3, PmGRF4, PmGRF5, PmGRF12, PmGRF16 and PmGRF21, were related to the formation of plant height in broomcorn millet.
Assuntos
Panicum , Filogenia , Panicum/química , Panicum/genética , Fatores de Transcrição/genética , Meristema , Genoma de PlantaRESUMO
A research strategy combining transcriptome data mining and experimental verification was adopted to identify the marker genes characterizing the syndrome elements of phlegm, stasis, and deficiency in steroid-induced osteonecrosis of the femoral head(SONFH). Firstly, the common differentially expressed gene sets of SONFH with the syndromes of phlegm-stasis obstructing collaterals, vessel obstruction, and liver-kidney deficiency were obtained from the clinical transcriptomic analysis of a previous study. The differential expression trend analysis and functional gene mining were then employed to predict the candidate marker gene sets representing phlegm, stasis, and deficiency. The whole blood samples from SONFH patients, whole blood samples from SONFH rats, and affected femoral head tissue samples were collected for qPCR, which aimed to determine the expression levels of the candidate marker genes mentioned above. Furthermore, the receiver operating characteristic curve(ROC) was established to objectively evaluate the syndrome differentiation effectiveness of the candidate marker genes mentioned above. The transcriptome data analysis results showed that the candidate marker genes for phlegm was ELOVL fatty acid elongase 6(ELOVL6), and those for stasis were ankyrin 1(ANK1), glycophorin A/B(GYPA/B), and Rh-associated glycoprotein(RHAG). The candidate marker genes for deficiency were solute carrier family 2 member 1(SLC2A1) and stomatin(STOM). The qPCR results showed that compared with that in the non-SONFH group, ELOVL6 had the lowest expression level in the peripheral blood of the SONFH patients with the syndrome of phlegm-stasis obstructing collaterals(P<0.05). Compared with that in the normal control group, ELOVL6 had the lowest expression level in the peripheral blood and affected femoral head tissue of SONFH rats modeled for 4 weeks(P<0.01), and it showed better syndrome differentiation effectiveness of rats modeled for 4 weeks(AUC=0.850, P=0.006) than at other modeling time points(8, 12, 16, and 21 weeks, AUC of 0.689, 0.766, 0.588, and 0.662, respectively). Compared with that in the non-SONFH group, the expression levels of ANK1, GYPA, and RHAG were the lowest in the peripheral blood of SONFH patients with the vessel obstruction syndrome(P<0.05). The expression levels of the three genes were the lowest in the peripheral blood and affected femoral head tissue of SONFH rats modeled for 12 weeks(P<0.05, P<0.01), and their syndrome differentiation effectiveness in the rats modeled for 12 weeks(GYPA: AUC=0.861, P=0.012; ANK1: AUC=0.855, P=0.006; RHAG: AUC=0.854, P=0.009) was superior to that for 4, 8, 16, and 21 weeks(GYPA: AUC=0.646, 0.573, 0.691, and 0.617, respectively; ANK: AUC1=0.630, 0.658, 0.657, and 0.585, respectively; RHAG: AUC=0.592, 0.511, 0.515, and 0.536, respectively). Compared with the non-SONFH group, both SLC2A1 and STOM had the lowest expression levels in the peripheral blood of patients with the syndrome of liver and kidney deficiency(P<0.05). Compared with the normal control group, their expression levels were the lowest in the peripheral blood and affected femoral head tissue of SONFH rats modeled for 21 weeks(P<0.05, except STOM in the peripheral blood of rats). Moreover, the syndrome differentiation effectiveness of SLC2A1 in the rats modeled for 21 weeks(AUC=0.806, P=0.009) was superior to that for 4, 8, 12, and 16 weeks(AUC=0.520, 0.580, 0.741, 0.774, respectively), and STOM was meaningless in syndrome differentiation. In summary, the candidate marker gene for phlegm in SONFH is ELOVL6; the candidate marker genes for stasis are GYPA, RHAG, and ANK1; the candidate marker gene for deficiency is SLC2A1. The results help to reveal the biological connotations of phlegm, stasis, and deficiency in SONFH at the genetic level.
Assuntos
Experimentação Animal , Osteonecrose , Doenças Vasculares , Humanos , Ratos , Animais , Transcriptoma , Cabeça do Fêmur , Síndrome , Esteroides/efeitos adversosRESUMO
The approach combining disease, syndrome, and symptom was employed to investigate the characteristic changes of blood stasis syndrome in a rat model of steroid-induced osteonecrosis of the femoral head(SONFH) during disease onset and progression. Seventy-two male SD rats were randomized into a healthy control group and a model group. The rat model of SONFH was established by injection of lipopolysaccharide(LPS) in the tail vein at a dose of 20 µg·kg~(-1)·d~(-1) on days 1 and 2 and gluteal intramuscular injection of methylprednisolone sodium succinate(MPS) at a dose of 40 mg·kg~(-1)·d~(-1) on days 3-5, while the healthy control group received an equal volume of saline. The mechanical pain test, tongue color RGB technique, gait detection, open field test, and inclined plane test were employed to assess hip pain, tongue color, limping, joint activity, and lower limb strength, respectively, at different time points within 21 weeks of modeling. At weeks 2, 4, 8, 12, 16, and 21 after modeling, histopathological changes of the femoral head were observed by hematoxylin-eosin(HE) staining and micro-CT scanning; four coagulation items were measured by rotational thromboelastometry; and enzyme-linked immunosorbent assay(ELISA) was employed to determine the levels of six blood lipids, vascular endothelial growth factor(VEGF), endothelin-1(ET-1), nitric oxide(NO), tissue-type plasminogen activator(t-PA), plasminogen activator inhibitor factor-1(PAI-1), bone gla protein(BGP), alkaline phosphatase(ALP), receptor activator of nuclear factor-κB(RANKL), osteoprotegerin(OPG), and tartrate-resistant acid phosphatase 5b(TRAP5b) in the serum, as well as the levels of 6-keto-prostaglandin 1α(6-keto-PGF1α) and thromboxane B2(TXB2) in the plasma. The results demonstrated that the pathological alterations in the SONFH rats were severer over time. The bone trabecular area ratio, adipocyte number, empty lacuna rate, bone mineral density(BMD), bone volume/tissue volume(BV/TV), trabecular thickness(Tb.Th), trabecular number(Tb.N), bone surface area/bone volume(BS/BV), and trabecular separation(Tb.Sp) all significantly increased or decreased over the modeling time after week 4. Compared with the healthy control group, the mechanical pain threshold, gait swing speed, stride, standing time, and walking cycle of SONFH rats changed significantly within 21 weeks after modeling, with the greatest difference observed 12 weeks after modeling. The time spent in the central zone, rearing score, and maximum tilt angle in the open field test of SONFH rats also changed significantly over the modeling time. Compared with the healthy control group, the R, G, and B values of the tongue color of the model rats decreased significantly, with the greatest difference observed 11 weeks after modeling. The levels of total cholesterol(TC), total triglycerides(TG), low-density lipoprotein-cholesterol(LDL-C), and apoprotein B(ApoB) in the SONFH rats changed significantly 4 and 8 weeks after modeling. The levels of VEGF, ET-1, NO, t-PA, PAI-1, 6-keto-PGF1α, TXB2, four coagulation items, and TXB2/6-keto-PGF1α ratio in the serum of SONFH rats changed significantly 4-16 weeks after modeling, with the greatest differences observed 12 weeks after modeling. The levels of BGP, TRAP5b, RANKL, OPG, and RANKL/OPG ratio in the serum of SONFH rats changed significantly 8-21 weeks after modeling. During the entire onset and progression of SONFH in rats, the blood stasis syndrome characteristics such as hyperalgesia, tongue color darkening, gait abnormalities, platelet, vascular, and coagulation dysfunctions were observed, which gradually worsened and then gradually alleviated in the disease course(2-21 weeks), with the most notable differences occurred around 12 weeks after modeling.
Assuntos
Necrose da Cabeça do Fêmur , Cabeça do Fêmur , Ratos , Masculino , Animais , Cabeça do Fêmur/diagnóstico por imagem , Cabeça do Fêmur/patologia , Inibidor 1 de Ativador de Plasminogênio/efeitos adversos , Fator A de Crescimento do Endotélio Vascular , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Necrose da Cabeça do Fêmur/patologia , Ratos Sprague-Dawley , Esteroides , Dor , ColesterolRESUMO
The assumption of reduced human error-related crashes with increasing levels of automation in pursuing Level 5 automation lacks empirical evidence. As automation levels rise, human error-induced safety hazards are anticipated to decrease, while machine error-induced hazards will increase. However, a quantitative index capturing this tradeoff is absent. Additionally, theoretical modeling of safety improvements during the transition to automated driving remains unexplored, particularly concerning reducing human error-related hazards. These limitations impede the understanding of safety from human and machine perspectives for Automated Vehicle (AV) specialists and manufacturers. This research addresses these gaps by investigating safety performance associations between human and machine factors using the "Human-Machine conflict reduction ratio" (H/M ratio), a novel metric. The study aims to establish safety improvements related to human errors under various automation levels. Sixty participants completed driving tasks on a driving simulator at Levels 0, 4, 3, and 2. Safety performance measures, including conflict frequency and severity, were computed. As a result, Level 4 exhibits the largest decrease (93.3%) compared to manual driving, followed by Level 2 (70.7%) and Level 3 (40.5%). The H/M ratio measures the tradeoff between reducing human and machine error-induced hazards, with Level 2 demonstrating the highest ratio, followed by Levels 4 and 3. Safety performance is evaluated by considering all possible types of human errors at each automation level. Theoretical models from a human factor's perspective are employed to estimate safety improvements at each level. This research contributes to a comprehensive understanding of safety in the "human-machine cooperative driving" phase, offering insights to AV industry practitioners and stakeholders.
Assuntos
Condução de Veículo , Humanos , Acidentes de Trânsito/prevenção & controle , Automação , Veículos AutônomosRESUMO
BACKGROUND: This study aimed to elucidate the mechanism by which wall shear stress (WSS) influences vascular walls, accounting for the susceptibility of intracranial aneurysms (IAs) to rupture. METHOD: We collected blood samples from the sacs of 24 ruptured and 28 unruptured IAs and analyzed the expression of chemokine CCL7 using enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression analyses were employed to assess clinical data, aneurysm morphology, and hemodynamics in both groups. Pearson correlation analysis investigated the relationship between CCL7 expression in aneurysm sac blood and WSS. Additionally, we established a bionic cell parallel plate co-culture shear stress model and a mouse low shear stress (LSS) model. The model was modulated using CCL7 recombinant protein, CCR1 inhibitor, and TAK1 inhibitor. We further evaluated CCL7 expression in endothelial cells and the levels of TAK1, NF-κB, IL-1ß, and TNF-α in macrophages. Subsequently, the intergroup differences in expression were calculated. RESULTS: CCL7 expression was significantly higher in the ruptured group compared to the unruptured group. Hemodynamic analysis indicated that WSS was an independent predictor of the risk of aneurysm rupture. A negative linear correlation was observed between CCL7 expression and WSS. Upon addition of CCL7 recombinant protein, upregulation of CCR1 expression and increased levels of p-TAK1 and p-p65 were observed. Treatment with CCR1 and TAK1 inhibitors reduced inflammatory cytokine expression in macrophages under LSS conditions. Overexpression of TAK1 significantly alleviated the inhibitory effects of CCR1 inhibitors on p-p65 and inflammatory cytokines. CONCLUSION: LSS prompts endothelial cells to secrete CCL7, which, upon binding to the macrophage surface receptor CCR1, stimulates the release of macrophage inflammatory factors via the TAK1/NF-κB signaling pathway. This process exacerbates aneurysm wall inflammation and increases the risk of aneurysm rupture.
Assuntos
Aneurisma Roto , Aneurisma Intracraniano , Animais , Camundongos , NF-kappa B , Células Endoteliais , Hemodinâmica/fisiologia , Inflamação , Citocinas , Proteínas RecombinantesRESUMO
Biochar (BC) has a strong potential for activating arsenic (As) in soil; thus, the phytoremediation efficiency of As-polluted soils is enhanced with Pteris vittata L. A pot experiment was conducted to investigate the potential of BC to assist in phytoremediation with P. vittata. The effects of BC on physicochemical properties, available As, enzyme activities, and the bacterial community in the rhizosphere soil were investigated, and the biomass, physiology, and As uptake of P. vittata were analyzed. The results indicated that applying BC facilitated available As in the P. vittata rhizosphere soil, and the phytoremediation efficiency percentage increased in the As-polluted soils, such as 3.80% and 8.01% under the 2% and 5% BC treatments compared to the control, respectively. Phytoremediation with P. vittata and BC significantly improved soil organic matter content, available N, P, and K, enzyme activities, and the bacterial community. BC promoted Streptomyces (26.6-54.2%) and Sphingomonas (12.3-30.8%) abundance which regulated the growth and As uptake by P. vittata. Moreover, applying BC increased the biomass, and As uptake by P. vittata. Overall, BC strengthened the phytoremediation of As-polluted soils by improving soil pH, nutrient concentrations, enzyme activities, bacterial community structure, and soil arsenic activation, growth, and absorption by P. vittata.
Assuntos
Arsênio , Carvão Vegetal , Pteris , Poluentes do Solo , Arsênio/análise , Solo/química , Poluentes do Solo/análise , Biodegradação Ambiental , BactériasRESUMO
Volatile organic compounds (VOCs) contamination at the groundwater may cause vapor intrusion and pose significant threats to human health. As a novel low-carbon mitigation technology, a horizontal permeable reactive barrier (HPRB) is proposed to remove the VOC vapor in the vadose zone and mitigate the vapor intrusion risk. To estimate the performance of HPRB in the contaminated site with a non-uniform source, a transient two-dimensional analytical model is developed in this study to simulate the VOC vapor migration and oxidation processes in the layered soil. The analytical model is verified against the experimental results and numerical simulation first and the parameter study is then conducted. The HPRB has good performance for the contaminated sites involving factors including deep source and local soil with low effective diffusivity. To consider the vertical heterogeneity of the local soil, the traditional equivalent homogeneity method has limitations in considering the horizontal migration of VOC vapor and is not suitable for the two-dimensional model. On the contrary, the artificial layered method based on the proposed analytical model has better accuracy and is recommended to be adopted in practice. Leading to the exponential decrease in the VOC vapor concentration at the ground surface, increasing the thickness of HPRB is an effective measure to enhance the performance of HPRB. The fitting exponential function can be applied to determine the minimum design value of the thickness of HPRB in practice.
RESUMO
This study investigated the concentrations of atmospheric pollutants in the urban area of Suzhou from May to June, 2017-2021. The variation characteristics and annual changes of ozone (O3), nitrogen oxide (NOx), total oxidant (Ox), carbon monoxide (CO), and volatile organic compounds (VOCs) were analyzed. The O3 formation mechanism and its annual changes were studied using an Observation-Based Model (OBM), and VOCs source apportionments and their trends were discussed. The results indicated that â The volume fractions of Ox and the concentrations of NOx and CO have decreased in the urban area of Suzhou in recent years, while the volume fractions of VOCs have increased, and sufficient photochemical conditions for O3 formation still existed during polluted days. â¡ The O3-NOx-VOCs sensitivity in Suzhou was in the VOCs-limited regime. The long-term reduction ratio between VOCs and NOx should not be less than 5:1, and aromatics and alkenes were the critical VOCs for mitigating O3 pollution. ⢠The results of VOCs source apportionment revealed that industrial emissions, gasoline vehicle exhaust, and diesel engine exhaust were the major sources of VOC emissions in Suzhou. Industrial emissions and solvent usage declined from 2017 to 2021; however, gasoline vehicle exhaust and gasoline evaporation, which possess higher O3 formation potential(OFP), increased significantly. ⣠The OFP source apportionments results indicated that controlling VOC emissions from solvent usage and gasoline vehicle exhaust is crucial for O3 pollution control in Suzhou.
RESUMO
High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part. ALDH1A3 (aldehyde dehydrogenase 1 family member A3) is a key enzyme for acetyl-CoA production involving aggressive behaviors of cancers. However, ALDH1A3's effects and molecular mechanisms in HGSOC remain to be clarified. Using RNA-seq and publicly available datasets, ALDH1A3 was found to be highly expressed in HGSOC, and associated with poor survival. Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin. ALDH1A3 expression in HGSOC cells was found to be increased by hypoxia, but decreased by HIF-1α inhibitor KC7F2. The dual-luciferase reporter assay showed that the increased transcriptional activity of ALDH1A3 induced by HIF-1α overexpression was reduced by KC7F2. In addition, PITX1 (paired like homeodomain 1) was identified to be inhibited by ALDH1A3 knockdown, and PITX1 depletion inhibited cell proliferation. The mechanistic studies showed that ALDH1A3 knockdown reduced the acetylation of histone 3 lysine 27 (H3K27ac). Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.
Assuntos
Carcinogênese , Neoplasias Ovarianas , Feminino , Humanos , Carcinogênese/genética , Transformação Celular Neoplásica , Neoplasias Ovarianas/genética , Epigênese Genética , AcetilaçãoRESUMO
Purpose: This study aimed to demonstrate the correlations between the altered functional connectivity patterns in the triple-network model and cognitive impairment in patients with cerebral small vascular disease (CSVD). Methods: Resting-state functional magnetic resonance imaging data were obtained from 22 patients with CSVD and 20 healthy controls. The resting-state data were analyzed using independent component analysis and functional network connectivity (FNC) analysis to explore the functional alterations in the intrinsic triple-network model including the salience network (SN), default mode network (DMN), and central executive network (CEN), and their correlations with the cognitive deficits and clinical observations in the patients with CSVD. Results: Compared to the healthy controls, the patients with CSVD exhibited increased connectivity patterns in the CEN-DMN and decreased connectivity patterns in the DMN-SN, CEN-SN, intra-SN, and intra-DMN. Significant negative correlations were detected between the intra-DMN connectivity pattern and the Montreal Cognitive Assessment (MoCA) total scores (r = -0.460, p = 0.048) and MoCA abstraction scores (r = -0.565, p = 0.012), and a positive correlation was determined between the intra-SN connectivity pattern and the MoCA abstraction scores (r = 0.491, p = 0.033). Conclusions: Our study findings suggest that the functional alterations in the triple-network model are associated with the cognitive deficits in patients with CSVD and shed light on the importance of the triple-network model in the pathogenesis of CSVD.
RESUMO
Cd0.3Pb0.7S (CdPbS) aqueous quantum dots (AQDs) made with 3-mercaptoproprionic acid (MPA) as a ligand have the advantages of emitting near-infrared light, well above 800 nm, that completely circumvents interference from tissue autofluorescence and have significant amounts of ligands for bioconjugation. However, retaining the right amount of MPA became a challenge when using CdPbS AQDs for bioimaging because retaining too much MPA could lead to significant nonspecific staining in cell imaging while insufficient MPA could cause AQDs instability in biological systems. Here we examined PEGylation (i.e. chemically linking amine-functionalized polyethylene glycol (PEG)) to modify MPA on the AQDs surface to improve AQDs stability and reduce nonspecific staining. In addition, for conjugation with antibodies, a bifunctional PEG with a carboxyl functionality was used to permit chemical linkage of a PEG to an antibody on the other end. It was found that performing PEGylation at the thiol concentration where the zeta potential becomes saturated stabilized the CdPbS AQDs suspension and reduced nonspecific binding to cells. Furthermore, with the bifunctional PEG, the CdPbS AQDs were conjugated with antibodies and the AQD-Ab conjugates were shown to stain cancer cells specifically against normal cells with a signal-to-noise ratio of 8.
Assuntos
Pontos Quânticos , Cádmio , Chumbo , Diagnóstico por Imagem , Anticorpos , PolietilenoglicóisRESUMO
BACKGROUND: The incidence of invasive fungal diseases (IFDs), represented by Candida albicans infection, is increasing year by year. However, clinically available antifungal drugs are very limited and encounter challenges such as limited efficacy, drug resistance, high toxicity, and exorbitant cost. Therefore, there is an urgent need for new antifungal drugs. PURPOSE: This study aims to find new antifungal compounds from plants, preferably those with good activity and low toxicity, and reveal their antifungal targets. METHODS: In vitro antifungal activities of compounds were investigated using broth microdilution method, spot assay, hyphal growth assay and biofilm formation assay. Synergistic effects were assessed using broth microdilution checkerboard technique. In vivo antifungal activities were evaluated using Galleria mellonella and murine candidiasis models. Cytotoxicity of compounds was investigated using Cell Counting Kit-8 (CCK-8). Discovery and validation of antifungal targets of compounds were conducted by using monoallelic knockout library of C. albicans, haploinsufficiency profiling (HIP), thermal shift assay (TSA), enzyme inhibitory effect assay, molecular docking, and in vitro and in vivo antifungal studies. RESULTS: 814 plant products were screened, among which petroselinic acid (PeAc) was found as an antifungal molecule. As a rare fatty acid isolated from coriander (Coriandrum sativum), carrot (Daucus carota) and other plants of the Apiaceae family, PeAc had not previously been found to have antifungal effects. In this study, PeAc was revealed to inhibit the growth of various pathogenic fungi, exhibited synergistic effects with fluconazole (FLC), inhibited the formation of C. albicans hyphae and biofilms, and showed antifungal effects in vivo. PeAc was less toxic to mammalian cells. Fructose-1,6-bisphosphate aldolase (Fba1p) was identified as a target of PeAc by using HIP, TSA, enzyme inhibitory effect assay and molecular docking methods. PeAc exerted antifungal effects more effectively on fba1Δ/FBA1 than wild-type (WT) strain both in vitro and in vivo. CONCLUSIONS: PeAc is an effective and low toxic antifungal compound. The target of PeAc is Fba1p. Fba1p is a promising target for antifungal drug development.
RESUMO
(1) Background: MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation remains an important predictive biomarker in high-grade gliomas (HGGs). The influence of necrosis on the fidelity of MGMT promoter (MGMTp) hypermethylation testing is currently unknown. Therefore, our study aims to evaluate the effect of varying degrees of necrosis on MGMTp status, as determined by pyrosequencing, in a series of primary and recurrent HGGs; (2) Methods: Within each case, the most viable blocks (assigned as 'true' MGMTp status) and the most necrotic block were determined by histopathology review. MGMTp status was determined by pyrosequencing. Comparisons of MGMTp status were made between the most viable and most necrotic blocks. (3) Results: 163 samples from 64 patients with HGGs were analyzed. MGMTp status was maintained in 84.6% of primary and 78.3% of recurrent HGGs between the most viable and necrotic blocks. A threshold of ≥60% tumor cellularity was established at which MGMTp status was unaltered, irrespective of the degree of necrosis. (4) Conclusions: MGMTp methylation status, as determined by pyrosequencing, does not appear to be influenced by necrosis in the majority of cases at a cellularity of at least 60%. Further investigation into the role of intratumoral heterogeneity on MGMTp status will increase our understanding of this predictive marker.
RESUMO
Enzymes catalyzing peptide macrocyclization are important biochemical tools in drug discovery. The three-residue cyclophane-forming enzymes (3-CyFEs) are an emerging family of post-translational modifying enzymes that catalyze the formation of three-residue peptide cyclophanes. In this report, we introduce three additional 3-CyFEs, including ChlB, WnsB, and FnnB, that catalyze cyclophane formation on Tyr, Trp, and Phe, respectively. To understand the promiscuity of these enzymes and those previously reported (MscB, HaaB, and YxdB), we tested single amino acid substitutions at the three-residue motif of modification (Ω1X2X3, Ω1 = aromatic). Collectively, we observe that substrate promiscuity is observed at the Ω1 and X2 positions, but a greater specificity is observed for the X3 residue. Two nonnative cyclophane products were characterized showing a Phe-C3 to Arg-Cß and His-C2 to Pro-Cß cross-links, respectively. We also tested the leader dependence of selected 3-CyFEs and show that a predicted helix region is important for cyclophane formation. These results demonstrate the biocatalytic potential of these maturases and allow rational design of substrates to obtain a diverse array of genetically encoded 3-residue cyclophanes.
Assuntos
Ciclofanos , Peptídeos , Sequência de Aminoácidos , Ciclização , Peptídeos/química , Processamento de Proteína Pós-TraducionalRESUMO
Background: The occurrence rate of distal anterior cerebral artery (DACA) aneurysms is relatively low, primarily due to their deep-seated location, which makes surgical clamping challenging. The objective of this study was to investigate the efficacy and safety of computed tomography (CT) navigation-assisted clipping of DACA aneurysms compared to traditional clipping without navigation. Methods: A retrospective cohort study involving retrospective data collection was performed. The retrospective analysis was conducted on 139 patients with ruptured DACA aneurysms who underwent clipping. From January 2013 to November 2021, 164 patients were retrieved at the Department of Neurosurgery, Renmin Hospital of Wuhan University. The inclusion criteria were patients diagnosed with DACA aneurysms via CT angiography (CTA) or digital subtraction angiography (DSA), those with complete clinical data, and those who underwent craniotomy for aneurysm clipping. Meanwhile, the exclusion criteria were as follows: aneurysm recurrence, traumatic brain injury or surgery history, blood disorders or recent anticoagulant use, and severe organ dysfunction. Data on gender, age, Hunt-Hess grade, Fisher grade, modified Rankin Scale (mRS) score, aneurysm location, hospitalization time, aneurysm found time (the duration from incision to aneurysm discovery), and intraoperative bleeding volume were collected from medical records and neurosurgical databases. Patients were followed up in the clinic or by telephone in May 2022. All patients were divided into a navigation group or a traditional group for statistical analysis. Results: No statistically significant differences were observed in age, sex, Fisher grade, Hunt-Hess grade, hospitalization time, or aneurysm site between the navigation group and traditional group (P>0.05). Intraoperative blood loss was lower in the navigation group than in the traditional group {370 [280-460] vs. 430 [310-610] mL, P=0.045}. Patients in the traditional group had a shorter aneurysm found time than did those in the navigation group {49 [42-53] vs. 79 [63-84] min, P<0.001}. There was no significant difference in the mRS score at hospital discharge (P=0.336) or follow-up (P=0.157) between the two groups. Conclusions: CT neuronavigation-assisted microsurgery for clipping DACA aneurysms may improve surgical accuracy, shorten the time to locate aneurysms, and reduce intraoperative blood loss. Although no significant difference in prognosis was observed, this technique shows promise as a safe and effective alternative to traditional clipping without navigation.