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1.
Cereb Cortex ; 34(5)2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38741271

RESUMEN

This study investigates abnormalities in cerebellar-cerebral static and dynamic functional connectivity among patients with acute pontine infarction, examining the relationship between these connectivity changes and behavioral dysfunction. Resting-state functional magnetic resonance imaging was utilized to collect data from 45 patients within seven days post-pontine infarction and 34 normal controls. Seed-based static and dynamic functional connectivity analyses identified divergences in cerebellar-cerebral connectivity features between pontine infarction patients and normal controls. Correlations between abnormal functional connectivity features and behavioral scores were explored. Compared to normal controls, left pontine infarction patients exhibited significantly increased static functional connectivity within the executive, affective-limbic, and motor networks. Conversely, right pontine infarction patients demonstrated decreased static functional connectivity in the executive, affective-limbic, and default mode networks, alongside an increase in the executive and motor networks. Decreased temporal variability of dynamic functional connectivity was observed in the executive and default mode networks among left pontine infarction patients. Furthermore, abnormalities in static and dynamic functional connectivity within the executive network correlated with motor and working memory performance in patients. These findings suggest that alterations in cerebellar-cerebral static and dynamic functional connectivity could underpin the behavioral dysfunctions observed in acute pontine infarction patients.


Asunto(s)
Infartos del Tronco Encefálico , Cerebelo , Imagen por Resonancia Magnética , Vías Nerviosas , Puente , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cerebelo/fisiopatología , Cerebelo/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Vías Nerviosas/diagnóstico por imagen , Puente/diagnóstico por imagen , Puente/fisiopatología , Infartos del Tronco Encefálico/fisiopatología , Infartos del Tronco Encefálico/diagnóstico por imagen , Anciano , Adulto , Corteza Cerebral/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen
2.
Quant Imaging Med Surg ; 14(4): 2840-2856, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38617178

RESUMEN

Background: Accelerated magnetic resonance imaging sequences reconstructed using the vendor-provided Recon deep learning algorithm (DL-MRI) were found to be more likely than conventional magnetic resonance imaging (MRI) sequences to detect subacromial (SbA) bursal thickening. However, the extent of this thickening was not extensively explored. This study aimed to compare the image quality of DL-MRI with conventional MRI sequences reconstructed via conventional pipelines (Conventional-MRI) for shoulder examinations and evaluate the effectiveness of DL-MRI in accurately demonstrating the degree of SbA bursal and subcoracoid (SC) bursal thickening. Methods: This prospective cross-sectional study enrolled 41 patients with chronic shoulder pain who underwent 3-T MRI (including both Conventional-MRI and accelerated MRI sequences) of the shoulder between December 2022 and April 2023. Each protocol consisted of oblique axial, coronal, and sagittal images, including proton density-weighted imaging (PDWI) with fat suppression (FS) and oblique coronal T1-weighted imaging (T1WI) with FS. The image quality and degree of artifacts were assessed using a 5-point Likert scale for both Conventional-MRI and DL-MRI. Additionally, the degree of SbA and SC bursal thickening, as well as the relative signal-to-noise ratio (rSNR) and relative contrast-to-noise ratio (rCNR) were analyzed using the paired Wilcoxon test. Statistical significance was defined as P<0.05. Results: The utilization of accelerated sequences resulted in a remarkable 54.7% reduction in total scan time. Overall, DL-MRI exhibited superior image quality scores and fewer artifacts compared to Conventional-MRI. Specifically, DL-MRI demonstrated significantly higher measurements of SC bursal thickenings in the oblique sagittal PDWI sequence compared to Conventional-MRI [3.92 (2.83, 5.82) vs. 3.74 (2.92, 5.96) mm, P=0.028]. Moreover, DL-MRI exhibited higher detection of SbA bursal thickenings in the oblique coronal PDWI sequence [2.61 (1.85, 3.46) vs. 2.48 (1.84, 3.25) mm], with a notable trend towards significant differences (P=0.071). Furthermore, the rSNRs of the muscle in DL-MRI images were significantly higher than those in Conventional-MRI images across most sequences (P<0.001). However, the rSNRs of bone on Conventional-MRI of oblique axial and oblique coronal PDWI sequences showed adverse results [oblique axial: 1.000 (1.000, 1.000) vs. 0.444 (0.367, 0.523); and oblique coronal: 1.000 (1.000, 1.000) vs. 0.460 (0.387, 0.631); all P<0.001]. Additionally, all DL-MRI images exhibited significantly greater rSNRs and rCNRs compared to accelerated MRI sequences reconstructed using traditional pipelines (P<0.001). Conclusions: In conclusion, the utilization of DL-MRI enhances image quality and improves diagnostic capabilities, making it a promising alternative to Conventional-MRI for shoulder imaging.

3.
Materials (Basel) ; 17(8)2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38673177

RESUMEN

Lead halide perovskites (LHPs) containing organic parts are emerging optoelectronic materials with a wide range of applications thanks to their high optical absorption, carrier mobility, and easy preparation methods. They possess spin-dependent properties, such as strong spin-orbit coupling (SOC), and are promising for spintronics. The Rashba effect in LHPs can be manipulated by a magnetic field and a polarized light field. Considering the surfaces and interfaces of LHPs, light polarization-dependent optoelectronics of LHPs has attracted attention, especially in terms of spin-dependent photocurrents (SDPs). Currently, there are intense efforts being made in the identification and separation of SDPs and spin-to-charge interconversion in LHP. Here, we provide a comprehensive review of second-order nonlinear photocurrents in LHP in regard to spintronics. First, a detailed background on Rashba SOC and its related effects (including the inverse Rashba-Edelstein effect) is given. Subsequently, nonlinear photo-induced effects leading to SDPs are presented. Then, SDPs due to the photo-induced inverse spin Hall effect and the circular photogalvanic effect, together with photocurrent due to the photon drag effect, are compared. This is followed by the main focus of nonlinear photocurrents in LHPs containing organic parts, starting from fundamentals related to spin-dependent optoelectronics. Finally, we conclude with a brief summary and future prospects.

4.
Br J Pharmacol ; 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38613153

RESUMEN

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

5.
Materials (Basel) ; 17(3)2024 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-38591439

RESUMEN

In natural kaolinite lattices, Al3+ can potentially be substituted by cations such as Mg2+, Ca2+, and Fe3+, thereby influencing its adsorption characteristics towards rare earth elements like Sc3+. Density functional theory (DFT) has emerged as a crucial tool in the study of adsorption phenomena, particularly for understanding the complex interactions of rare earth elements with clay minerals. This study employed DFT to investigate the impact of these three dopant elements on the adsorption of hydrated Sc3+ on the kaolinite (001) Al-OH surface. We discerned that the optimal adsorption configuration for hydrated Sc3+ is Sc(H2O)83+, with a preference for adsorption at the deprotonated Ou sites. Among the dopants, Mg doping exhibited superior stability with a binding energy of -4.311 eV and the most negative adsorption energy of -1104.16 kJ/mol. Both Mg and Ca doping enhanced the covalency of the Al-O bond, leading to a subtle shift in the overall density of states towards higher energies, thereby augmenting the reactivity of the O atoms. In contrast, Fe doping caused a pronounced shift in the density of states towards lower energies. Compared to the undoped kaolinite, Mg and Ca doping further diminished the adsorption energy of hydrated Sc3+ and increased its coordination number, while Fe doping elevated the adsorption energy. This study offers profound insights into understanding the role of dopant elements in the adsorption of hydrated Sc3+ on kaolinite.

6.
Biochem Biophys Res Commun ; 714: 149970, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38663097

RESUMEN

Movement dynamics in the nucleus involve various biological processes, including DNA repair, which is crucial for cancer prevention. Changes in the movement of the components of the nucleus indicate the changes in movement dynamics in the nucleus. In Schizosaccharomyces pombe, the inner nuclear membrane protein Bqt4 plays an essential role in attaching telomeres to the nuclear envelope. We observed that the deletion of bqt4+ caused a significant decrease in the mean square displacement (MSD) calculated from the distance between the nucleolar center and spindle pole body (SPB), hereafter referred to as MSD(SPB-Nucleolus). The MSD(SPB-Nucleolus) decrease in bqt4Δ was microtubule-dependent. The Rap1-binding ability loss mutant, bqt4F46A, and nonspecific DNA-binding ability mutants, bqt43E-A, did not exhibit an MSD(SPB-Nucleolus) decrease compared to the WT. Moreover, the bqt43E-Arap1Δ double mutant and 1-262 amino acids truncated mutant bqt4ΔN (263-432), which does not have either Rap1-binding or nonspecific DNA-binding abilities, did not exhibit the MSD(SPB-Nucleolus) decrease to the same extent as bqt4Δ. These results suggest that the unknown function of Bqt4 in the C-terminal domain is essential for the maintenance of the pattern of relative movement between SPB and the nucleolus.


Asunto(s)
Nucléolo Celular , Proteínas de Unión al ADN , Proteínas Nucleares , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Cuerpos Polares del Huso , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Nucléolo Celular/metabolismo , Cuerpos Polares del Huso/metabolismo , Mutación , Microtúbulos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Unión Proteica
7.
Artículo en Inglés | MEDLINE | ID: mdl-38687553

RESUMEN

Chiral plasmonic nanocrystals have recently attracted increasing attention in circular polarization-dependent photocatalysis driven by hot carriers. While being concealed in traditional ensemble measurements, the individual chiral photocatalytic activity of nanocrystals can exclusively be revealed by directly correlating the circular differential photocurrent response to helical morphologies using single-particle techniques. Herein, we develop a method named circular differential photocurrent mapping (CDPM) and demonstrate that CDPM can be used to characterize the circular differential hot electron (CDHE) response from individual Au nanohelicoids (AuNHs) on a TiO2 photoanode in a photoelectrochemical cell. The single-particle circular differential scattering and CDHE measurements were interpreted with calculations performed on a model in direct correlation to the helical morphologies of the nanocrystal. While CDHE response was found inactive at a dipolar resonance of 750 nm, helicity-convoluted sites of HE generation were identified on the AuNH at a specific higher-order mode of 550 nm, resulting in a significant response of CDHE in association with the handedness of the AuNH. Details of circular differential contributions were further resolved by examining the efficiencies of individual AuNHs in terms of g-factors. Our study provides a powerful microscopic method at the single-particle level for the photocatalytic characterization of chiral nanocrystals, gaining fundamental insights into the photocatalysis of chirality, especially toward plasmon-induced asymmetrical photochemistry or photoelectrochemistry.

8.
Comput Biol Med ; 172: 108252, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38493604

RESUMEN

Gout, a painful condition marked by elevated uric acid levels often linked to the diet's high purine and alcohol content, finds a potential treatment target in xanthine oxidase (XO), a crucial enzyme for uric acid production. This study explores the therapeutic properties of alkaloids extracted from sunflower (Helianthus annuus L.) receptacles against gout. By leveraging computational chemistry and introducing a novel R-based clustering algorithm, "TriDimensional Hierarchical Fingerprint Clustering with Tanimoto Representative Selection (3DHFC-TRS)," we assessed 231 alkaloid molecules from sunflower receptacles. Our clustering analysis pinpointed six alkaloids with significant gout-targeting potential, particularly emphasizing the fifth cluster's XO inhibition capabilities. Through molecular docking and the BatchDTA prediction model, we identified three top compounds-2-naphthylalanine, medroxalol, and fenspiride-with the highest XO affinity. Further molecular dynamics simulations assessed their enzyme active site interactions and binding free energies, employing MM-PBSA calculations. This investigation not only highlights the discovery of promising compounds within sunflower receptacle alkaloids via LC-MS but also introduces medroxalol as a novel gout treatment candidate, showcasing the synergy of computational techniques and LC-MS in drug discovery.


Asunto(s)
Etanolaminas , Gota , Helianthus , Helianthus/metabolismo , Ácido Úrico/metabolismo , Ácido Úrico/uso terapéutico , Simulación del Acoplamiento Molecular , Inhibidores Enzimáticos/farmacología , Gota/tratamiento farmacológico , Xantina Oxidasa/química , Xantina Oxidasa/metabolismo
9.
Science ; 383(6689): 1337-1343, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38513024

RESUMEN

The introduction of molecularly woven three-dimensional (3D) covalent organic framework (COF) crystals into polymers of varying types invokes different forms of contact between filler and polymer. Whereas the combination of woven COFs with amorphous and brittle polymethyl methacrylate results in surface interactions, the use of the liquid-crystalline polymer polyimide induces the formation of polymer-COF junctions. These junctions are generated by the threading of polymer chains through the pores of the nanocrystals, thus allowing for spatial arrangement of polymer strands. This offers a programmable pathway for unthreading polymer strands under stress and leads to the in situ formation of high-aspect-ratio nanofibrils, which dissipate energy during the fracture. Polymer-COF junctions also strengthen the filler-matrix interfaces and lower the percolation thresholds of the composites, enhancing strength, ductility, and toughness of the composites by adding small amounts (~1 weight %) of woven COF nanocrystals. The ability of the polymer strands to closely interact with the woven framework is highlighted as the main parameter to forming these junctions, thus affecting polymer chain penetration and conformation.

10.
J Opt Soc Am A Opt Image Sci Vis ; 41(2): 349-354, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38437349

RESUMEN

A simple twin-core D-shape photonic crystal fiber sensor based on surface plasmon resonance (SPR) is designed for the measurement of refractive indices (RI). The twin-core D-shape structure enhances the SPR effect, and the M g F 2-Au dual-layer film narrows the linewidth in the loss spectrum, consequently improving both the sensitivity and figure of merit (FOM). The properties of the sensor are analyzed by the finite element method. In the RI range of 1.32-1.42, the maximum wavelength sensitivity, FOM, and resolution are 62,000 nm/RIU, 1281R I U -1, and 1.61×10-6, respectively.

11.
Sci Rep ; 14(1): 5709, 2024 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-38459090

RESUMEN

There is increasing evidence of abnormal neurodevelopmental outcomes in preterm infants with low-grade intraventricular hemorrhage (IVH). The purpose of the study was to explore whether brain microstructure and volume are associated with neuro-behavioral outcomes at 40 weeks corrected gestational age in preterm infants with low-grade IVH. MR imaging at term-equivalent age (TEA) was performed in 25 preterm infants with mild IVH (Papile grading I/II) and 40 control subjects without IVH. These subjects all had neonatal behavioral neurological assessment (NBNA) at 40 weeks' corrected age. Microstructure and volume evaluation of the brain were performed by using diffusion kurtosis imaging (DKI) and Synthetic MRI. Correlations among microstructure parameters, volume, and developmental outcomes were explored by using Spearman's correlation. In preterm infants with low-grade IVH, the volume of brain parenchymal fraction (BPF) was reduced. In addition, mean kurtosis (MK), fractional anisotropy (FA), radial kurtosis (RK), axial kurtosis (AK) in several major brain regions were reduced, while mean diffusivity (MD) was increased (P < 0.05). BPF, RK in the cerebellum, MK in the genu of the corpus callosum, and MK in the thalamus of preterm infants with low-grade IVH were associated with lower NBNA scores (r = 0.831, 0.836, 0.728, 0.772, P < 0.05). DKI and Synthetic MRI can quantitatively evaluate the microstructure alterations and brain volumes in preterm infants with low-grade IVH, which provides clinicians with a more comprehensive and accurate neurobehavioral assessment of preterm infants with low-grade IVH.


Asunto(s)
Enfermedades del Prematuro , Recien Nacido Prematuro , Lactante , Humanos , Recién Nacido , Encéfalo/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/complicaciones , Imagen de Difusión Tensora/métodos , Imagen por Resonancia Magnética , Enfermedades del Prematuro/diagnóstico por imagen
12.
Acad Radiol ; 31(5): 2074-2084, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38185571

RESUMEN

RATIONALE AND OBJECTIVES: This study employed tract-based spatial statistics (TBSS) to investigate abnormalities in the white matter microstructure among children with autism spectrum disorder (ASD). Additionally, an eXtreme Gradient Boosting (XGBoost) model was developed to effectively classify individuals with ASD and typical developing children (TDC). METHODS AND MATERIALS: Multi-shell diffusion weighted images were acquired from 62 children with ASD and 44 TDC. Using the Pydesigner procedure, diffusion tensor (DT), diffusion kurtosis (DK), and white matter tract integrity (WMTI) metrics were computed. Subsequently, TBSS analysis was applied to discern differences in these diffusion parameters between ASD and TDC groups. The XGBoost model was then trained using metrics showing significant differences, and Shapley Additive explanations (SHAP) values were computed to assess the feature importance in the model's predictions. RESULTS: TBSS analysis revealed a significant reduction in axonal diffusivity (AD) in the left posterior corona radiata and the right superior corona radiata. Among the DK indicators, mean kurtosis, axial kurtosis, and kurtosis fractional anisotropy were notably increased in children with ASD, with no significant difference in radial kurtosis. WMTI metrics such as axonal water fraction, axonal diffusivity of the extra-axonal space (EAS_AD), tortuosity of the extra-axonal space (EAS_TORT), and diffusivity of intra-axonal space (IAS_Da) were significantly increased, primarily in the corpus callosum and fornix. Notably, there was no significant difference in radial diffusivity of the extra-axial space (EAS_RD). The XGBoost model demonstrated excellent classification ability, and the SHAP analysis identified EAS_TORT as the feature with the highest importance in the model's predictions. CONCLUSION: This study utilized TBSS analyses with multi-shell diffusion data to examine white matter abnormalities in pediatric autism. Additionally, the developed XGBoost model showed outstanding performance in classifying ASD and TDC. The ranking of SHAP values based on the XGBoost model underscored the significance of features in influencing model predictions.


Asunto(s)
Trastorno del Espectro Autista , Imagen de Difusión Tensora , Aprendizaje Automático , Sustancia Blanca , Humanos , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno del Espectro Autista/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Masculino , Femenino , Preescolar , Imagen de Difusión Tensora/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Niño , Interpretación de Imagen Asistida por Computador/métodos
13.
World Neurosurg ; 183: e813-e817, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38218435

RESUMEN

BACKGROUND: The high incidence of nonunion in osteoporosis vertebral compression fractures (OVCFs) among the elderly population is a significant concern. But the hypothesis about etiopathogenesis of the intravertebral cleft (IVC) is not convincing. This study aims to investigate the association between spinopelvic parameters and IVC. METHODS: Patients with single segment IVC or healed vertebral compression fracture (HVCF) were retrospectively recruited for the study. Patients with IVC were assigned to the IVC group, the others were assigned to the HVCF group. We estimated whether IVC or HVCF locates the vertebra inflection point on lumbar lateral radiography. Distance between the sagittal line passing through the anterosuperior corner of S1and the center of the vertebra of healed fracture or with IVC (DSVA) and sacral slope (SS) were measured on lumbar lateral plain films. Intergroup spinopelvic parameters were analyzed. analysis to identify independent variables associated with IVC incidence. The receiver operating characteristics (ROC) curve was generated to identify the optimal cut-off point for statistically significant variables. RESULTS: Sixty-five patients were included in the study. Thirty patients (mean age: 74 ± 7.16 years) had single-level IVC, and 35 patients (mean age: 67.71 ± 7.30 years) had single-level HVCF. Age, body mass index (BMI), and DSVA were statistically different between the groups (all P < 0.05). The occurrence of IVC was related to the DSVA in the multivariate logistic regression analysis (OR = 0.73, P < 0.05). CONCLUSIONS: According to the results of this study, large DSVA was a risk factor for IVC formation in patients with OVCFs. Patients with global spinal malalignment should be actively observed during conservative treatment.


Asunto(s)
Fracturas por Compresión , Osteoporosis , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Humanos , Anciano , Anciano de 80 o más Años , Persona de Mediana Edad , Fracturas por Compresión/complicaciones , Fracturas de la Columna Vertebral/complicaciones , Estudios Retrospectivos , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/complicaciones , Osteoporosis/complicaciones , Osteoporosis/diagnóstico por imagen
14.
Curr Biol ; 34(4): 808-824.e6, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38295797

RESUMEN

Many motor control systems generate multiple movements using a common set of muscles. How are premotor circuits able to flexibly generate diverse movement patterns? Here, we characterize the neuronal circuits that drive the distinct courtship songs of Drosophila melanogaster. Male flies vibrate their wings toward females to produce two different song modes-pulse and sine song-which signal species identity and male quality. Using cell-type-specific genetic reagents and the connectome, we provide a cellular and synaptic map of the circuits in the male ventral nerve cord that generate these songs and examine how activating or inhibiting each cell type within these circuits affects the song. Our data reveal that the song circuit is organized into two nested feedforward pathways with extensive reciprocal and feedback connections. The larger network produces pulse song, the more complex and ancestral song form. A subset of this network produces sine song, the simpler and more recent form. Such nested organization may be a common feature of motor control circuits in which evolution has layered increasing flexibility onto a basic movement pattern.


Asunto(s)
Drosophila melanogaster , Drosophila , Animales , Femenino , Masculino , Drosophila/fisiología , Drosophila melanogaster/fisiología , Cortejo , Conducta Sexual Animal/fisiología , Neuronas/fisiología
15.
J Immunother Cancer ; 12(1)2024 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-38272564

RESUMEN

BACKGROUND: Cryoablation is a minimally invasive option for patients with medically inoperable non-small cell lung cancer (NSCLC) and can trigger abscopal immune-regulatory effects. However, it remains unclear how cryoablation affects the host-level immune response in NSCLC. In this study, we investigated the local and systemic immunological effects of cryoablation and the potential of combining cryoablation with programmed cell death protein 1 (PD-1) blockade to boost immunotherapy efficacy in NSCLC. METHODS: We first investigated systemic immunological effects induced by cryoablation in patients with early-stage NSCLC. Subsequently, we explored cryoablation-induced antitumor immunity and the underlying biological mechanisms using KP (Kras G12D/+, Tp53 -/-) mutant lung cancer cell allograft mouse models. Moreover, the synergistic efficacy of cryoablation and PD-1 blockade was explored in both mouse models and patients with unresectable NSCLC. RESULTS: We found that cryoablation significantly increased circulating CD8+ T cell subpopulations and proinflammatory cytokines in patients with early-stage NSCLC. In lung cancer cell allograft mouse models, we demonstrated that cryoablation resulted in abscopal growth inhibition of contralateral, non-ablated tumors. Integrated analysis of bulk, single-cell RNA and T cell receptor (TCR) sequencing data revealed that cryoablation reprogrammed the intratumoral immune microenvironment and increased CD8+ T cell infiltration with higher effector signature, interferon (IFN) response, and cytolytic activity. Mechanistically, cryoablation promoted antitumor effect through the STING-dependent type I IFN signaling pathway, and type I IFN signaling blockade attenuated this antitumor effect. We also found that the combination of PD-1 blockade with cryoablation further inhibited tumor growth compared with either treatment alone in an allograft mouse model. Moreover, the combination therapy induced notable tumor suppression and CD8+ T cell infiltration in patients with unresectable NSCLC. CONCLUSIONS: Our results provide mechanistic insights into how cryoablation triggers the antitumor immune effect in lung cancer, thereby potentiating programmed cell death ligand 1 (PD-L1)/PD-1 blockade efficacy in the clinical treatment of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Criocirugía , Interferón Tipo I , Neoplasias Pulmonares , Ratones , Animales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1 , Inmunoterapia/métodos , Microambiente Tumoral
16.
ACS Appl Mater Interfaces ; 16(4): 4375-4394, 2024 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-38185858

RESUMEN

RNA interference-based gene therapy has led to a strategy for spinal cord injury (SCI) therapy. However, there have been high requirements regarding the optimal gene delivery vector for siRNA-based SCI gene therapy. Here, we developed an injectable and photocurable lipid nanoparticle GelMA (PLNG) hydrogel scaffold for controlled dual siRNA delivery at the SCI wound site. The prepared PLNG scaffold could efficiently protect and retain the bioactivity of the siRNA nanocomplex. It facilitated sustainable siRNA release along with degradation in 7 days. After loading dual siRNA targeting phosphatase and tensin homologue (PTEN) and macrophage migration inhibitory factor (MIF) simultaneously, the locally administered siRNAs/PLNG scaffold efficiently improved the Basso mouse scale (BMS) score and recovered ankle joint movement and plantar stepping after treatment with only three doses. We further proved that the siRNAs/PLNG scaffold successfully regulated the activities of neurons, microglia, and macrophages, thus promoting neuron axon regeneration and remyelination. The protein array results suggested that the siRNAs/PLNG scaffold could increase the expression of growth factors and decrease the expression of inflammatory factors to regulate neuroinflammation in SCI and create a neural repair environment. Our results suggested that the PLNG scaffold siRNA delivery system is a potential candidate for siRNA-based SCI therapy.


Asunto(s)
Axones , Traumatismos de la Médula Espinal , Ratones , Animales , Regeneración Nerviosa , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/tratamiento farmacológico , Neuronas , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico
17.
J Am Chem Soc ; 146(4): 2835-2844, 2024 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-38236722

RESUMEN

We have developed two series of amine-functionalized zirconium (Zr) metal-organic framework-808 (MOF-808), which were produced by postsynthetic modifications to have either amino acids coordinated to Zr ions (MOF-808-AAs) or polyamines covalently bound to the chloro-functionalized structure (MOF-808-PAs). These MOF variants were comprehensively characterized by liquid-state 1H nuclear magnetic resonance (NMR) measurements and potentiometric acid-base titration to determine the amounts of amines, energy-dispersive X-ray spectroscopy to assess the extent of covalent substitution by polyamines, powder X-ray diffraction analysis to verify the maintenance of the MOF crystallinity and structure after postsynthetic modifications, nitrogen sorption isotherm measurements to confirm retention of the porosity, and water sorption isotherm measurements to find the water uptake in the pores of each member of the series. Evaluation and testing of these compounds in direct air capture (DAC) of CO2 showed improved CO2 capture performance for the functionalized forms, especially under humid conditions: In dry conditions, the l-lysine- and tris(3-aminopropyl)amine-functionalized variants, termed as MOF-808-Lys and MOF-808-TAPA, exhibited the highest CO2 uptakes at 400 ppm, measuring 0.612 and 0.498 mmol g-1, and further capacity enhancement was achieved by introducing 50% relative humidity, resulting in remarkable uptakes of 1.205 and 0.872 mmol g-1 corresponding to 97 and 75% increase compared to the dry uptakes, respectively. The mechanism underlying the enhanced uptake efficiency was revealed by 13C solid-state NMR and temperature-programmed desorption measurements, indicating the formation of bicarbonate species, and therefore a stoichiometry of 1:1 CO2 to each amine site.

18.
Mol Pharm ; 21(1): 267-282, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38079527

RESUMEN

Messenger ribonucleic acid (mRNA)-based gene therapy has great potential for cancer gene therapy. However, the effectiveness of mRNA in cancer therapy needs to be further improved, and the delivery efficiency and instability of mRNA limit the application of mRNA-based products. Both the delivery efficiency can be elevated by cell-penetrating peptide modification, and the immune response can be enhanced by tumor cell lysate stimulation, representing an advantageous strategy to expand the effectiveness of mRNA gene therapy. Therefore, it is vital to exploit a vector that can deliver high-efficiency mRNA with codelivery of tumor cell lysate to induce specific immune responses. We previously reported that DMP cationic nanoparticles, formed by the self-assembly of DOTAP and mPEG-PCL, can deliver different types of nucleic acids. DMP has been successfully applied in gene therapy research for various tumor types. Here, we encapsulated tumor cell lysates with DMP nanoparticles and then modified them with a fused cell-penetrating peptide (TAT-iRGD) to form an MLSV system. The MLSV system was loaded with encoded Bim mRNA, forming the MLSV/Bim complex. The average size of the synthesized MLSV was 191.4 nm, with a potential of 47.8 mV. The MLSV/mRNA complex promotes mRNA absorption through caveolin-mediated endocytosis, with a transfection rate of up to 68.6% in B16 cells. The MLSV system could also induce the maturation and activation of dendritic cells, obviously promoting the expression of CD80, CD86, and MHC-II both in vitro and in vivo. By loading the encoding Bim mRNA, the MLSV/Bim complex can inhibit cell proliferation and tumor growth, with inhibition rates of up to 87.3% in vitro. Similarly, the MLSV/Bim complex can inhibit tumor growth in vivo, with inhibition rates of up to 78.7% in the B16 subcutaneous tumor model and 63.3% in the B16 pulmonary metastatic tumor model. Our results suggest that the MLSV system is an advanced candidate for mRNA-based immunogene therapy.


Asunto(s)
Péptidos de Penetración Celular , Melanoma , Nanopartículas Multifuncionales , Nanopartículas , Humanos , Melanoma/genética , Melanoma/terapia , Transfección , Terapia Genética , Línea Celular Tumoral
19.
Acad Radiol ; 31(4): 1326-1335, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37863778

RESUMEN

RATIONALE AND OBJECTIVES: This study aimed to evaluate the technical success rate and stiffness measurement reliability of two specific hepatic magnetic resonance elastography (MRE) sequences dedicated to solving susceptibility artifacts in patients with various degrees of hepatic iron overload. MATERIALS AND METHODS: Thirty-seven patients with iron-overloaded liver confirmed by R2* value measurement who underwent two-dimensional (2D) spin-echo (SE) MRE and 2D SE-echo-planar-imaging (EPI) MRE were reviewed retrospectively. According to four categories based on R2* value (mild, moderate, severe elevation, and extremely severe iron overload), we compared the success rate, quality score, and liver stiffness of the two sequences. In addition, Spearman's correlation was performed to evaluate the relationship between the R2* value and liver stiffness. RESULTS: The overall success rates of SE MRE and SE-EPI MRE in patients with hepatic iron overload were 91.89% and 78.38%, respectively, and 100% and 78.57%, respectively, for severe elevation iron overload. In all patients, the MRE quality scores were 54 and 48 for SE MRE and SE-EPI MRE, respectively (P = 0.107). There were no significant differences in liver stiffness measurements between the two MRE methods in patients with mild, moderate, and severe elevation iron-overloaded livers (P > 0.6 for all), respectively. For both MRE methods, R2* value had no significant effect on the liver stiffness measurements (correlation coefficient <0.1, P >0.6 for both). CONCLUSION: In the mild and moderate elevation iron-overloaded liver, both SE MRE and fast SE-EPI MRE can provide successful and reliable liver stiffness measurement. In severe elevation iron-overloaded livers, SE MRE may be a better choice than SE-EPI MRE.


Asunto(s)
Diagnóstico por Imagen de Elasticidad , Sobrecarga de Hierro , Humanos , Diagnóstico por Imagen de Elasticidad/métodos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/patología , Imagen por Resonancia Magnética/métodos , Imagen Eco-Planar/métodos , Sobrecarga de Hierro/diagnóstico por imagen , Sobrecarga de Hierro/patología , Hierro
20.
Adv Mater ; 36(13): e2309171, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38104281

RESUMEN

Narrow bandgap cubic formamidine perovskite (α-FAPbI3) is widely studied for its potential to achieve record­breaking efficiency. However, its high preparation difficulty caused by lattice instability is criticized. A popular strategy for stabilizing the α-FAPbI3 lattice is to replace intrinsic FA+ or I- with smaller ions of MA+, Cs+, Rb+, and Br-, whereas this generally leads to broadened optical bandgap and phase separation. Studies show that ions substitution-free phase-pure α-FAPbI3 can achieve intrinsic phase stability. However, the challenging preparation of high-quality films has hindered its further development. Here, a facile synthesis of high-quality MA+, Cs+, Rb+, and Br--free phase-pure α-FAPbI3 perovskite film by a new solution modification strategy is reported. This enables the activation of lead-iodine (Pb─I) frameworks by forming the coated Pb⋯O network, thus simultaneously promoting spontaneous homogeneous nucleation and rapid phase transition from δ to α phase. As a result, the efficient and stable phase-pure α-FAPbI3 PSC is obtained through a one-step method without antisolvent treatment, with a record efficiency of 23.15% and excellent long-term operating stability for 500 h under continuous light stress.

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