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1.
Angew Chem Int Ed Engl ; : e202412040, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39023217

RESUMO

Chlororaphens A and B are structurally unique non-canonical C17 sesquiterpenoids from Pseudomonas chlororaphis that are made by two SAM-dependent methyltransferases and a type I terpene synthase. This study addresses the mechanism of their formation in isotopic labelling experiments and DFT calculations. The results demonstrate an astonishing complexity with distribution of labellings within a cyclopentane core that is reversely connected to two acyclic fragments in chlororaphen A and B. In addition, the uptake of up to 14 deuterium atoms from D2O was observed. These findings are explainable by a repeated late stage multistep rearrangement sequence. The absolute configurations of the chlororaphens and their biosynthetic intermediates were elucidated in stereoselective labelling experiments.

2.
Spectrochim Acta A Mol Biomol Spectrosc ; 322: 124805, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-39003827

RESUMO

A novel fluorimetric ratiometric probe of green and eco-friendily nitrogen-enriched, oxygen-doped carbon nanodots (Cnanodots) was prepared for the quantitative analysis of mercury(II) (HgII) and nitrofurantoin (Nit) in the environmental sewage. The Cnanodots exhibits dual-emission peaks respectively at 345 and 445 nm under 285 nm excitation, with excitation-independent properties. Unexpectedly, this Cnanodots displays two obvious ratiometric responses to HgII and Nit through decreasing the signal at 345 nm and remaining invariable at 445 nm. Experimental results confirm that the highly sensitive analysis of HgII and Nit are achieved respectively based on matching energy-level electron transfer and inner filter effect mechanisms. The fluorescence (FL) ratiometric intensity of [FL345nm/FL445nm] expresses a good linear relationship with the concentration of HgII in the scope of 0.01-20 µM, while the logarithm of [Log(FL0345nm-FL345nm)] on the quenching degree of the probe by Nit also shows a good linear correlation within the range of 0.01-100 µM. The detection limits were calculated to be 4.14 nM for HgII, and 7.84 nM for Nit. Moreover, recovery experiments of Cnanodots for HgII and Nit sensing in real sewage samples obtained satisfactory results, comfirming the feasibility of practical application.

3.
Nat Commun ; 15(1): 5902, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39003266

RESUMO

Analogous of pixels to two-dimensional pictures, voxels-in the form of either small cubes or spheres-are the basic building blocks of three-dimensional objects. However, precise manipulation of viscoelastic bio-ink voxels in three-dimensional space represents a grand challenge in both soft matter science and biomanufacturing. Here, we present a voxelated bioprinting technology that enables the digital assembly of interpenetrating double-network hydrogel droplets made of polyacrylamide/alginate-based or hyaluronic acid/alginate-based polymers. The hydrogels are crosslinked via additive-free and biofriendly click reaction between a pair of stoichiometrically matched polymers carrying norbornene and tetrazine groups, respectively. We develop theoretical frameworks to describe the crosslinking kinetics and stiffness of the hydrogels, and construct a diagram-of-state to delineate their mechanical properties. Multi-channel print nozzles are developed to allow on-demand mixing of highly viscoelastic bio-inks without significantly impairing cell viability. Further, we showcase the distinctive capability of voxelated bioprinting by creating highly complex three-dimensional structures such as a hollow sphere composed of interconnected yet distinguishable hydrogel particles. Finally, we validate the cytocompatibility and in vivo stability of the printed double-network scaffolds through cell encapsulation and animal transplantation.


Assuntos
Resinas Acrílicas , Alginatos , Bioimpressão , Ácido Hialurônico , Hidrogéis , Bioimpressão/métodos , Hidrogéis/química , Alginatos/química , Animais , Ácido Hialurônico/química , Resinas Acrílicas/química , Camundongos , Tinta , Impressão Tridimensional , Humanos , Engenharia Tecidual/métodos , Sobrevivência Celular , Materiais Biocompatíveis/química
4.
Int Immunopharmacol ; 138: 112554, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38968861

RESUMO

BACKGROUND: Human placental mesenchymal stromal cells (hPMSCs) are known to limit graft-versus-host disease (GVHD). CD8+CD122+PD-1+Tregs have been shown to improve the survival of GVHD mice. However, the regulatory roles of hPMSCs in this subgroup remain unclear. Here, the regulatory mechanism of hPMSCs in reducing liver fibrosis in GVHD mice by promoting CD8+CD122+PD-1+Tregs formation and controlling the balance of IL-6 and IL-10 were explored. METHODS: A GVHD mouse model was constructed using C57BL/6J and BALB/c mice and treated with hPMSCs. LX-2 cells were explored to study the effects of IL-6 and IL-10 on the activation of hepatic stellate cells (HSCs). The percentage of CD8+CD122+PD-1+Tregs and IL-10 secretion were determined using FCM. Changes in hepatic tissue were analysed by HE, Masson, multiple immunohistochemical staining and ELISA, and the effects of IL-6 and IL-10 on LX-2 cells were detected using western blotting. RESULTS: hPMSCs enhanced CD8+CD122+PD-1+Treg formation via the CD73/Foxo1 and promoted IL-10, p53, and MMP-8 levels, but inhibited IL-6, HLF, α-SMA, Col1α1, and Fn levels in the liver of GVHD mice through CD73. Positive and negative correlations of IL-6 and IL-10 between HLF were found in liver tissue, respectively. IL-6 upregulated HLF, α-SMA, and Col1α1 expression via JAK2/STAT3 pathway, whereas IL-10 upregulated p53 and inhibited α-SMA and Col1α1 expression in LX-2 cells by activating STAT3. CONCLUSIONS: hPMSCs promoted CD8+CD122+PD-1+Treg formation and IL-10 secretion but inhibited HSCs activation and α-SMA and Col1α1 expression by CD73, thus controlling the balance of IL-6 and IL-10, and alleviating liver injury in GVHD mice.

5.
Front Pharmacol ; 15: 1418465, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38983917

RESUMO

Background: ß-blockers have been widely used in patients with extensive cardiovascular disease (CVD) and have provided benefits. However, they are more likely to cause symptomatic bradycardia, hypotension, or glucose metabolism disorders, which may lead to an increased risk of atrial fibrillation (AF), but evidence is lacking. Aims: This study was to analyze the association between the use of ß-blockers and the risk of developing AF. Methods: This nationwide, prospective cohort study utilized data from the 2013-2020 National Health and Nutrition Examination Survey (NHANES). The patients were stratified into a ß-blocker treatment group (n = 2585) and a non-ß-blocker treatment group (n = 8525). Univariate and multivariate logistic regression analyses were performed to identify the relationship between ß-blockades and the risk of AF. Propensity matching analysis was used to balance patient baseline characteristics and to control for confounders. Results: A total of 11,110 subjects were included in this study (mean [SD] age, 59.89 [15.07] years; 5657 [49.7%] males). A total of 111/2585 subjects developed AF in the ß-blocker treatment group, and 75/8525 developed AF in the non-ß-blocker treatment group (incidence rate, 4.2% vs. 0.8%). Compared with the non-ß-blocker group, the ß-blocker group had an increased risk of incident AF (aOR, 2.339; 95% CI, 1.614-3.410). Some sensitivity analyses also revealed consistent findings of increased AF risk associated with ß-blocker treatment. Conclusion: The findings from this study suggest that ß-blocker treatment is associated with an increased risk of incident AF and may help physicians select a modest medication for patients while also assessing the risk of AF.

6.
Org Lett ; 26(28): 5888-5892, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38976793

RESUMO

New diterpenoids are accessible from non-natural FPP derivatives as substrates for an enzymatic elongation cyclization cascade using the geranylgeranyl pyrophosphate synthase (GGPPS) from Streptomyces cyaneofuscatus and the spata-13,17-diene synthase (SpS) from Streptomyces xinghaiensis. This approach led to four new biotransformation products including three new cyclododecane cores and a macrocyclic ether. For the first time, a 1,12-terpene cyclization was observed when shifting the central olefinic double bond toward the geminial methyl groups creating a nonconjugated 1,4-diene.


Assuntos
Alquil e Aril Transferases , Dimetilaliltranstransferase , Diterpenos , Streptomyces , Diterpenos/química , Diterpenos/metabolismo , Dimetilaliltranstransferase/metabolismo , Dimetilaliltranstransferase/química , Streptomyces/enzimologia , Streptomyces/química , Alquil e Aril Transferases/metabolismo , Alquil e Aril Transferases/química , Estrutura Molecular , Ciclização , Fosfatos de Poli-Isoprenil/química , Fosfatos de Poli-Isoprenil/metabolismo , Biotransformação
7.
Bioinformatics ; 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39041615

RESUMO

MOTIVATION: The gene content regulates the biology of an organism. It varies between species and between individuals of the same species. Although tools have been developed to identify gene content changes in bacterial genomes, none is applicable to collections of large eukaryotic genomes such as the human pangenome. RESULTS: We developed pangene, a computational tool to identify gene orientation, gene order and gene copy-number changes in a collection of genomes. Pangene aligns a set of input protein sequences to the genomes, resolves redundancies between protein sequences and constructs a gene graph with each genome represented as a walk in the graph. It additionally finds subgraphs, which we call bibubbles, that capture gene content changes. Applied to the human pangenome, pangene identifies known gene-level variations and reveals complex haplotypes that are not well studied before. Pangene also works with high-quality bacterial pangenome and reports similar numbers of core and accessory genes in comparison to existing tools. AVAILABILITY AND IMPLEMENTATION: Source code at https://github.com/lh3/pangene; pre-built pangene graphs can be downloaded from https://zenodo.org/records/8118576 and visualized at https://pangene.bioinweb.org.

8.
Small ; : e2403821, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38949043

RESUMO

Compared to the bulk heterojunction (BHJ) devices, the quasiplanar heterojunction (Q-PHJ) exhibits a more stable morphology and superior charge transfer performance. To achieve both high efficiency and long-term stability, it is necessary to design new materials for Q-PHJ devices. In this study, QxIC-CF3 and QxIC-CH3 are designed and synthesized for the first time. The trifluoromethylation of the central core exerts a modulatory effect on the molecular stacking pattern, leveraging the strong electrostatic potential and intermolecular interactions. Compared with QxIC-CH3, the single crystal structure reveals that QxIC-CF3 exhibits a more compact 2D linear stacking behavior. These benefits, combined with the separated electron and hole transport channels in Q-PHJ device, lead to increased charge mobility and reduced energy loss. The devices based on D18/QxIC-CF3 exhibit an efficiency of 18.1%, which is the highest power conversion efficiency (PCE) for Q-PHJ to date. Additionally, the thermodynamic stability of the active layer morphology enhances the lifespan of the aforementioned devices under illumination conditions. Specifically, the T80 is 420 h, which is nearly twice that of the renowned Y6-based BHJ device (T80 = 220 h). By combining the advantages of the trifluoromethylation and Q-PHJ device, efficient and stable organic solar cell devices can be constructed.

9.
Diabetes Metab ; 50(5): 101560, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38950855

RESUMO

AIM: To explore the relationships of multiple reproductive factors with type 2 diabetes mellitus (T2DM) risk and the joint effects of reproductive factors and genetic susceptibility. METHODS: We included 262,368 women without prevalent T2DM from the UK biobank. Cox proportional hazards regression models were employed to estimate the relationships of reproductive factors with T2DM risk and the joint effects of reproductive factors and genetic susceptibility. RESULTS: During a mean follow-up of 12.2 years, 8,996 T2DM cases were identified. Early menarche (<12 years, hazard ratio (HR) 1.08 [95 % confidence interval (CI) 1.02;1.13]), late menarche (≥15 years, HR 1.11 [1.04;1.17]), early menopause (<45 years, HR 1.20 [1.12;1.29]), short reproductive lifespan (<30 years, HR 1.25 [1.16;1.35]), hysterectomy (1.31, HR [1.23;1.40]), oophorectomy (HR 1.28 [1.20;1.36]), high parity (≥4, HR 1.25 [1.17;1.34]), early age at first live birth (<20 years, HR 1.23 [1.16;1.31]), miscarriage (HR 1.13 [1.07;1.19]), stillbirth (HR 1.14 [1.03;1.27]), and ever used hormonal replacement therapy (HR 1.19 [1.14;1.24]) were related to a higher T2DM risk, while ever used oral contraceptives (HR 0.93 [0.89;0.98]) was related to a lower T2DM risk. Furthermore, women with reproductive risk factors and high genetic risk had the highest T2DM risk compared to those with low genetic risk and without reproductive risk factors. CONCLUSION: Our findings show that multiple reproductive factors are related to T2DM risk, particularly in women with high genetic risk.

10.
Med Phys ; 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-39031641

RESUMO

BACKGROUNDS: When comparing the delivery of all beams per fraction (ABPF) to single beam per fraction (SBPF), it is observed that SBPF not only helps meet the FLASH dose threshold but also mitigates the uncertainty with beam switching in the FLASH effect. However, SBPF might lead to a higher biological equivalent dose in 2 Gy (EQD2) for normal tissues. PURPOSE: This study aims to develop an EQD2-based integrated optimization framework (EQD2-IOF), encompassing robust dose, delivery efficiency, and beam orientation optimization (BOO) for Bragg peak FLASH plans using the SBPF treatment schedule. The EQD2-IOF aims to enhance both dose sparing and the FLASH effect. METHODS: A superconducting gantry was employed for fast energy switching within 27 ms, while universal range shifters were utilized to improve beam current in the implementation of FLASH plans with five Bragg peak beams. To enhance dose delivery efficiency while maintaining plan quality, a simultaneous dose and spot map optimization (SDSMO) algorithm for single field optimization was incorporated into a Bayesian optimization-based auto-planning algorithm. Subsequently, a BOO algorithm based on Tabu search was developed to select beam angle combinations (BACs) for 10 lung cases. To simultaneously consider dose sparing and FLASH effect, a quantitative model based on dose-dependent dose modification factor (DMF) was used to calculate FLASH-enhanced dose distribution. The EQD2-IOF plan was compared to the plan optimized without SDSMO using BAC selected by a medical physicist (Manual plan) in the SBPF treatment schedule. Meanwhile, the mean EQD2 in the normal tissue was evaluated for the EQD2-IOF plan in both SBPF and ABPF treatment schedules. RESULTS: No significant difference was found in D2% and D98% of the target between EQD2-IOF plans and Manual Plans. When using a minimum DMF of 0.67 and a dose threshold of 4 Gy, EQD2-IOF plans showed a significant reduction in FLASH-enhanced EQD2mean of the ipsilateral lung and normal tissue by 10.5% and 11.5%, respectively, compared to Manual plans. For normal tissues that received a dose greater than 70% of the prescription dose, using a minimum DMF of 0.7 for FLASH sparing compensated for the increase in EQD2mean resulting from replacing ABPF with SBPF schedules. CONCLUSIONS: The EQD2-IOF can automatically optimize SBPF FLASH-RT plans to achieve optimal sparing of normal tissues. With an energy switching time of 27 ms, the loss of fractionate repairing using SBPF schedules in high-dose regions can be compensated for by the FLASH effect. However, when an energy switching time of 500 ms is utilized, the SBPF schedule needs careful consideration, as the FLASH effect diminishes with longer irradiation time.

11.
PLoS One ; 19(7): e0305163, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38976662

RESUMO

OBJECTIVE: To investigate the diagnostic value of D-dimer, platelet-lymphocyte rate (PLR) and CT signs for intestinal ischemia in patients with bowel obstruction. METHODS: We retrospectively analyzed the clinical and imaging data of 105 patients diagnosed with bowel obstruction, and performed univariate and multivariate analyses to determine the independent risk factors for intestinal ischemia in patients with bowel obstruction. Moreover, the receiver operating characteristic curve (ROC) was plotted to examine the diagnostic value of D-dimer, PLR and CT signs in patients with bowel obstruction. Besides, Kappa tests were used to assess inter-observer agreement. RESULTS: We included 56 men (53%) and 49 women (47%) with mean age of 66.05 ± 16 years. Univariate and multivariate analyses showed that D-dimer, PLR and two significant CT signs (i.e., increased unenhanced bowel-wall attenuation and mesenteric haziness) were independent risk factors for intestinal ischemia in patients with bowel obstruction. ROC analysis showed that the combined use of D-dimer, PLR and the said two CT signs had better performance than single indicators in predicting intestinal ischemia in patients with bowel obstruction. The area under the curve (AUC) of the joint model III was 0.925 [95%CI: 0.876-0.975], with a sensitivity of 79.2% [95CI%: 67.2-91.1] and a specificity of 91.2% [95%CI: 83.7-98.9]. CONCLUSION: The combined use of D-dimer, PLR and CT signs has high diagnostic value for intestinal ischemia in patients with bowel obstruction and will prompt surgical exploration to evaluate intestinal blood flow.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio , Obstrução Intestinal , Isquemia , Linfócitos , Tomografia Computadorizada por Raios X , Humanos , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Masculino , Feminino , Idoso , Obstrução Intestinal/sangue , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/etiologia , Obstrução Intestinal/diagnóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Isquemia/sangue , Curva ROC , Intestinos/irrigação sanguínea , Intestinos/patologia , Intestinos/diagnóstico por imagem , Plaquetas/patologia , Plaquetas/metabolismo , Contagem de Plaquetas , Contagem de Linfócitos , Idoso de 80 Anos ou mais , Fatores de Risco
12.
J Affect Disord ; 362: 485-492, 2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39009318

RESUMO

BACKGROUND: Major depression (MD) is recurrent and devastating mental disease with a high worldwide prevalence. Mounting evidence suggests neuroinflammation triggers cellular immune dysregulation, characterized by increased proportions of circulating monocytes, and T helper 17 cells and proinflammatory cytokines, thereby increasing susceptibility to MD. However, there is ambiguity in the findings of clinical studies that investigate CD4+ T regulatory (Treg) cells in MD. METHODS: The proportion of CD4+ Treg cell from blood mononuclear cells was examined using flow cytometry in healthy controls (HCs: n = 96) and patients with first (FEMD: n = 62) or recurrent (RMD: n = 41) disease episodes of MD at baseline (T0; hospital admission) and after a two-week antidepressant treatment (T14). All participants underwent comprehensive neuropsychological assessments. RESULTS: The initial scores on emotional assessments in patients with MD significantly differed from those of HCs. Both FEMD and RMD patients exhibited a significant decrease in CD4+ Treg cell proportion at baseline compared to HCs. Treg cell proportion rose significantly from T0 to T14 in FEMD patients, who responded to antidepressant therapy, whereas no significant changes were observed in FEMD patients in non-response as well as RMD patients. The improvement of 24-item Hamilton Depression Scale was correlate with changes of Treg cell proportion from T0 to T14 in FEMD patients in response, and the change in Treg cell proportion over a 14-day period exhibited an AUC curve of 0.710. CONCLUSIONS: A decrease in the proportion of CD4+ Treg cells points towards immune system abnormalities in patients with MD. Furthermore, our finding suggests that the immune activation state varies across different stages of depression.

13.
Radiother Oncol ; 199: 110438, 2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39013503

RESUMO

PURPOSE: To develop a combined radiomics and deep learning (DL) model in predicting radiation esophagitis (RE) of a grade ≥ 2 for patients with esophageal cancer (EC) underwent volumetric modulated arc therapy (VMAT) based on computed tomography (CT) and radiation dose (RD) distribution images. MATERIALS AND METHODS: A total of 273 EC patients underwent VMAT were retrospectively reviewed and enrolled from two centers and divided into training (n = 152), internal validation (n = 66), and external validation (n = 55) cohorts, respectively. Radiomic and dosiomic features along with DL features using convolutional neural networks were extracted and screened from CT and RD images to predict RE. The performance of these models was evaluated and compared using the area under curve (AUC) of the receiver operating characteristic curves (ROC). RESULTS: There were 5 and 10 radiomic and dosiomic features were screened, respectively. XGBoost achieved a best AUC of 0.703, 0.694 and 0.801, 0.729 with radiomic and dosiomic features in the internal and external validation cohorts, respectively. ResNet34 achieved a best prediction AUC of 0.642, 0.657 and 0.762, 0.737 for radiomics based DL model (DLR) and RD based DL model (DLD) in the internal and external validation cohorts, respectively. Combined model of DLD + Dosiomics + clinical factors achieved a best AUC of 0.913, 0.821 and 0.805 in the training, internal, and external validation cohorts, respectively. CONCLUSION: Although the dose was not responsible for the prediction accuracy, the combination of various feature extraction methods was a factor in improving the RE prediction accuracy. Combining DLD with dosiomic features was promising in the pretreatment prediction of RE for EC patients underwent VMAT.

15.
Artigo em Inglês | MEDLINE | ID: mdl-38836956

RESUMO

PURPOSE: After robotic-assisted total knee arthroplasty (RA-TKA) surgery, some patients still experience joint discomfort. We aimed to establish an effective machine learning model that integrates radiomic features extracted from computed tomography (CT) scans and relevant clinical information to predict patient satisfaction three months postoperatively following RA-TKA. MATERIALS AND METHODS: After careful selection, data from 142 patients were randomly divided into a training set (n = 99) and a test set (n = 43), approximately in a 7:3 ratio. A total of 1329 radiomic features were extracted from the regions of interest delineated in CT scans. The features were standardized using normalization algorithms, and the least absolute shrinkage and selection operator regression model was employed to select radiomic features with ICC > 0.75 and P < 0.05, generating the Rad-score as feature markers. Univariate and multivariate logistic regression was then used to screen clinical information (age, body mass index, operation time, gender, surgical side, comorbidities, preoperative KSS score, preoperative range of motion (ROM), preoperative and postoperative HKA angle, preoperative and postoperative VAS score) as potential predictive factors. The satisfaction scale ≥ 20 indicates patient satisfaction. Finally, three prediction models were established, focusing on radiomic features, clinical features, and their fusion. Model performance was evaluated using Receiver Operating Characteristic curves and decision curve analysis. RESULTS: In the training set, the area under the curve (AUC) of the clinical model was 0.793 (95% CI 0.681-0.906), the radiomic model was 0.854 (95% CI 0.743-0.964), and the combined radiomic-clinical model was 0.899 (95% CI 0.804-0.995). In the test set, the AUC of the clinical model was 0.908 (95% CI 0.814-1.000), the radiomic model was 0.709 (95% CI 0.541-0.878), and the combined radiomic-clinical model was 0.928 (95% CI 0.842-1.000). The AUC of the radiomic-clinical model was significantly higher than the other two models. The decision curve analysis indicated its clinical application value. CONCLUSION: We developed a radiomic-based nomogram model using CT imaging to predict the satisfaction of RA-TKA patients at 3 months postoperatively. This model integrated clinical and radiomic features and demonstrated good predictive performance and excellent clinical application potential.

16.
ACS Nano ; 18(27): 17586-17599, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38932624

RESUMO

Pulmonary drug delivery is critical for the treatment of respiratory diseases. However, the human airway surface presents multiple barriers to efficient drug delivery. Here, we report a bottlebrush poly(ethylene glycol) (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by a molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (∼1000) low molecular weight (∼1000 g/mol) polyethylene glycol (PEG) chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of ∼250 nm, a cross-section of ∼20 nm, and a hydrodynamic diameter of ∼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture-enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a carrier for pulmonary and mucosal drug delivery.


Assuntos
Portadores de Fármacos , Endocitose , Polietilenoglicóis , Humanos , Polietilenoglicóis/química , Portadores de Fármacos/química , Nanopartículas/química , Mucosa Respiratória/metabolismo , Mucosa Respiratória/citologia , Tamanho da Partícula , Sistemas de Liberação de Medicamentos , Proliferação de Células/efeitos dos fármacos
17.
Int J Biol Macromol ; 274(Pt 2): 133452, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38942414

RESUMO

Transdermal drug delivery refers to the administration of drugs through the skin, after which the drugs can directly act on or circulate through the body to the target organs or cells and avoid the first-pass metabolism in the liver and kidneys experienced by oral drugs, reducing the risk of drug poisoning. From the initial singular approach to transdermal drug delivery, there has been a shift toward combining multiple methods to enhance drug permeation efficiency and address the limitations of individual approaches. Technological advancements have also improved the accuracy of drug delivery. Optimizing insulin itself also enables its long-term release via needle-free injectors. In this review, the diverse transdermal delivery methods employed in insulin therapy and their respective advantages and limitations are discussed. By considering factors such as the principles of transdermal penetration, drug delivery efficiency, research progress, synergistic innovations among different methods, patient compliance, skin damage, and posttreatment skin recovery, a comprehensive evaluation is presented, along with prospects for potential novel combinatorial approaches. Furthermore, as insulin is a macromolecular drug, insights gained from its transdermal delivery may also serve as a valuable reference for the use of other macromolecular drugs for treatment.

18.
J Colloid Interface Sci ; 672: 299-310, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-38843682

RESUMO

Radical-nonradical co-dominant pathways have become a hot topic in advanced oxidation, but achieving this on transition metal sulfides (TMS) remains challenging because their inherently higher electron and spin densities always induce radicals rather than nonradicals. Herein, a biosurfactant layer (BLR) was introduced to redistribute the electron and spin structure of nanoscale iron sulfide (FeS), which allowed both radical and nonradical to co-dominate the catalytic reaction. The resulting BLR-encased FeS hybrid (BLR@FeS) exhibited satisfactory removal efficiency (98.5 %) for hydrogen peroxide (H2O2) activation, outperforming both the constituent components [FeS (70.9 %) and BLR (86.2 %)]. Advanced characterizations showed that C, O, N-related sites (-CO and -NC) in BLR attracted electrons in FeS due to their strong electronegativity and electron-withdrawing capacity, which not only decreased electron density in FeS, but also resulted in a shift of the Fe/S sites from the high-spin to the medium-spin state. The reaction routes established by the BLR@FeS/H2O2 system maintained desirable stability against environmental interferences such as common inorganic anions, humic acid and changes in pH. Our study provides a state-of-the-art, molecule-level understanding of tunable co-dominant pathways and expands the targeted applications in the field of advanced oxidation.

19.
Chem Commun (Camb) ; 60(55): 7041-7044, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38904208

RESUMO

Two terpene synthases from the pleuromutilin producing fungus Clitopilus passeckerianus were functionally characterised. The first enzyme CpTS1 produces the new diterpene clitopilene with a novel 6-6-5-5 tetracyclic skeleton, while the second enzyme CpTS2 makes the new sesquiterpene isopentalenene. The CpTS1 reaction mechanism was studied in depth using experimental and theoretical approaches.


Assuntos
Alquil e Aril Transferases , Diterpenos , Alquil e Aril Transferases/metabolismo , Diterpenos/química , Diterpenos/metabolismo , Sesquiterpenos/química , Sesquiterpenos/metabolismo , Pleuromutilinas
20.
Biomed Opt Express ; 15(6): 3699-3714, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38867787

RESUMO

Multi-modal eye disease screening improves diagnostic accuracy by providing lesion information from different sources. However, existing multi-modal automatic diagnosis methods tend to focus on the specificity of modalities and ignore the spatial correlation of images. This paper proposes a novel cross-modal retinal disease diagnosis network (CRD-Net) that digs out the relevant features from modal images aided for multiple retinal disease diagnosis. Specifically, our model introduces a cross-modal attention (CMA) module to query and adaptively pay attention to the relevant features of the lesion in the different modal images. In addition, we also propose multiple loss functions to fuse features with modality correlation and train a multi-modal retinal image classification network to achieve a more accurate diagnosis. Experimental evaluation on three publicly available datasets shows that our CRD-Net outperforms existing single-modal and multi-modal methods, demonstrating its superior performance.

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