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1.
Cereb Cortex ; 34(4)2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38610084

RESUMEN

The application of wearable magnetoencephalography using optically-pumped magnetometers has drawn extensive attention in the field of neuroscience. Electroencephalogram system can cover the whole head and reflect the overall activity of a large number of neurons. The efficacy of optically-pumped magnetometer in detecting event-related components can be validated through electroencephalogram results. Multivariate pattern analysis is capable of tracking the evolution of neurocognitive processes over time. In this paper, we adopted a classical Chinese semantic congruity paradigm and separately collected electroencephalogram and optically-pumped magnetometer signals. Then, we verified the consistency of optically-pumped magnetometer and electroencephalogram in detecting N400 using mutual information index. Multivariate pattern analysis revealed the difference in decoding performance of these two modalities, which can be further validated by dynamic/stable coding analysis on the temporal generalization matrix. The results from searchlight analysis provided a neural basis for this dissimilarity at the magnetoencephalography source level and the electroencephalogram sensor level. This study opens a new avenue for investigating the brain's coding patterns using wearable magnetoencephalography and reveals the differences in sensitivity between the two modalities in reflecting neuron representation patterns.


Asunto(s)
Electroencefalografía , Magnetoencefalografía , Femenino , Masculino , Humanos , Semántica , Potenciales Evocados , Análisis Multivariante , China
2.
Neuroimage ; 296: 120661, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38838840

RESUMEN

Optically pumped magnetometer magnetoencephalography (OPM-MEG) holds significant promise for clinical functional brain imaging due to its superior spatiotemporal resolution. However, effectively suppressing metallic artifacts, particularly from devices such as orthodontic braces and vagal nerve stimulators remains a major challenge, hindering the wider clinical application of wearable OPM-MEG devices. A comprehensive analysis of metal artifact characteristics from time, frequency, and time-frequency perspectives was conducted for the first time using an OPM-MEG device in clinical medicine. This study focused on patients with metal orthodontics, examining the modulation of metal artifacts by breath and head movement, the incomplete regular sub-Gaussian distribution, and the high absolute power ratio in the 0.5-8 Hz band. The existing metal artifact suppression algorithms applied to SQUID-MEG, such as fast independent component analysis (FastICA), information maximization (Infomax), and algorithms for multiple unknown signal extraction (AMUSE), exhibit limited efficacy. Consequently, this study introduced the second-order blind identification (SOBI) algorithm, which utilized multiple time delays for the component separation of OPM-MEG measurement signals. We modified the time delays of the SOBI method to improve its efficacy in separating artifact components, particularly those in the ultralow frequency range. This approach employs the frequency-domain absolute power ratio, root mean square (RMS) value, and mutual information methods to automate the artifact component screening process. The effectiveness of this method was validated through simulation experiments involving four subjects in both resting and evoked experiments. In addition, the proposed method was also validated by the actual OPM-MEG evoked experiments of three subjects. Comparative analyses were conducted against the FastICA, Infomax, and AMUSE algorithms. Evaluation metrics included normalized mean square error, normalized delta band power error, RMS error, and signal-to-noise ratio, demonstrating that the proposed method provides optimal suppression of metal artifacts. This advancement holds promise for enhancing data quality and expanding the clinical applications of OPM-MEG.


Asunto(s)
Artefactos , Magnetoencefalografía , Humanos , Magnetoencefalografía/métodos , Magnetoencefalografía/instrumentación , Adulto , Femenino , Masculino , Algoritmos , Metales , Procesamiento de Señales Asistido por Computador , Adulto Joven , Encéfalo/fisiología
3.
Biochem Biophys Res Commun ; 715: 150007, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38678783

RESUMEN

Smad4, a critical mediator of TGF-ß signaling, plays a pivotal role in regulating various cellular functions, including immune responses. In this study, we investigated the impact of Smad4 knockout specifically in macrophages on anti-tumor immunity, focusing on lung metastasis of B16 melanoma cells. Using a mouse model with Smad4 knockout in macrophages established via Lyz2-cre mice and Smad4 flox/flox mice, we demonstrated a significant inhibition of B16 metastasis in the lungs. Interestingly, the inhibition of tumor growth was found to be independent of adaptive immunity, as no significant changes were observed in the numbers or activities of T cells, B cells, or NK cells. Instead, Smad4 knockout led to the emergence of an MCHIIlow CD206high subset of lung interstitial macrophages, characterized by enhanced phagocytosis function. Our findings highlight the crucial role of Smad4 in modulating the innate immune response against tumors and provide insights into potential therapeutic strategies targeting lung interstitial macrophages to enhance anti-tumor immunity.


Asunto(s)
Neoplasias Pulmonares , Melanoma Experimental , Fagocitosis , Proteína Smad4 , Animales , Ratones , Línea Celular Tumoral , Pulmón/patología , Pulmón/inmunología , Pulmón/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/patología , Melanoma Experimental/patología , Melanoma Experimental/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis/genética , Proteína Smad4/deficiencia , Proteína Smad4/genética , Proteína Smad4/metabolismo
4.
Small ; : e2311217, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38396321

RESUMEN

Amidst the escalating quest for clean energy, the hydrogen evolution reaction (HER) in acidic conditions has taken center stage, catalyzing the search for advanced electrocatalysts. The efficacy of these materials is predominantly dictated by the active site density on their surfaces. The propensity is leveraged for monolayer architectures to introduce defects, enhancing surface area, and increasing active sites. Doping enhances defects and fine-tunes catalyst activity. In this vein, defect-enriched monolayer nanosheets doped with nickel and a trace amount of ruthenium in VS2 (SL-Ni-Ru-VS2 ) are engineered and characterized. Evaluation in 0.5 m H2 SO4 solution unveils that the catalyst achieves overpotentials as low as 20 and 41 mV at current densities of -10 and -100 mA cm⁻2 . Impressively, the catalyst maintains a mass activity of 13.08 A mg⁻¹Ru , even with minimal Ru incorporation, indicating exceptional catalytic efficiency. This monolayer catalyst sustains its high activity at lower overpotentials, demonstrating its practical applicability. The comprehensive analysis, which combines experimental data and computational simulations, indicates that the co-doping of Ni and Ru enhances the electrocatalytic properties of VS2 . This research offers a strategic framework for crafting cutting-edge electrocatalysts specifically designed for enhanced performance in the HER.

5.
Microb Pathog ; 192: 106709, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38810766

RESUMEN

This study prepared a novel monoclonal antibody (MAb) against mink enteritis parvovirus (MEV) and identified its antigen epitope. The antibody subclass is identified as IgG1, the titers of the MAb is up to 1:1 × 106 and keeps stably after low-temperature storage for 9 months or 11 passages of the MAb cells. The MAb can specifically recognize MEV in the cells in IFA, but not Aleutian disease virus (ADV) or canine distemper virus (CDV). Its antigen epitope was identified as a polypeptide containing 5 key amino acids (378YAFGR382) and the homology in 20 MEV strains, 4 canine parvovirus strains, and 4 feline panleukopenia virus strains was 100%. This study supplies a biological material for developing new methods to detect MEV.


Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Antivirales , Virus del Moquillo Canino , Epítopos , Virus de la Enteritis del Visón , Animales , Anticuerpos Monoclonales/inmunología , Epítopos/inmunología , Virus de la Enteritis del Visón/inmunología , Virus del Moquillo Canino/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Visón/inmunología , Inmunoglobulina G/inmunología , Virus de la Enfermedad Aleutiana del Visón/inmunología , Parvovirus Canino/inmunología , Virus de la Panleucopenia Felina/inmunología , Mapeo Epitopo , Ratones , Ratones Endogámicos BALB C , Enteritis Viral del Visón/inmunología
6.
Opt Lett ; 49(8): 1892-1895, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38621032

RESUMEN

We experimentally demonstrate the highly-efficient nonlocal erasing and writing of ferroelectric domains using a femtosecond laser in lithium niobate. Based on the induction of a focused infrared femtosecond laser without any relative displacement or additional treatment, the original multiple ferroelectric domains can be either erased (erasing operation) or elongated (writing operation) simultaneously in the crystal, depending on the laser focusing depth and the laser pulse energy. In the erasing operation, the original multiple ferroelectric domains can be cleared completely by just one laser induction, while in the writing operation, the average length of the ferroelectric domains can be elongated up to 235 µm by three laser inductions. A model has been proposed in which a thermoelectric field and a space charge field are used cooperatively to successfully explain the mechanism of nonlocal erasing and writing. This method greatly improves the efficiency and flexibility of tailoring ferroelectric domain structures, paving the way to large-scale all-optical industrial production for nonlinear photonic crystals and nonvolatile ferroelectric domain wall memories.

7.
Opt Lett ; 49(4): 1097-1100, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38359262

RESUMEN

We experimentally extend the nonlinear Gaussian to flat-top beam shaping from one to two dimensions through a three-dimensional nonlinear photonic crystal. Employing a near-infrared femtosecond laser, we induce a modification inside lithium niobate to achieve a second-order nonlinear optical coefficient modulation in three dimensions. The flat-topped truncation of wavefront has been adjusted in a mutual perpendicular coordinate separately. Among the generated flat-topped beams, the optimal flatness is 97.1%, and the nonlinear conversion efficiency is 10-2 at the peak power of 37 kW with the interaction length of 630 µm. By adding an extra dimension, our work simultaneously enables full-wavefront flat-top distribution and nonlinear frequency conversion.

8.
Inorg Chem ; 63(13): 5961-5971, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38494631

RESUMEN

Titanium-oxo cluster (TOC)-based metal-organic frameworks (MOFs) have received considerable attention in recent years due to their ability to expand the application of TOCs to fields that require highly stable frameworks. Herein, a new cyclic TOC formulated as [Ti6O6(OiPr)8(TTFTC)(phen)2]2 (1, where TTFTC = tetrathiafulvalene tetracarboxylate and phen = phenanthroline) was crystallographically characterized. TOC 1 takes a rectangular ring structure with two phen-modified Ti6 clusters as the width and two TTFTC ligands as the length. An intracluster ligand-to-ligand (TTF-to-phen) charge transfer in 1 was found for TOCs for the first time. Compound 1 undergoes topotactic conversion to generate stable TOC-MOF P1, in which the rectangular framework in 1 formed by a TOC core and ligands is retained, as verified by comprehensive characterization. P1 shows an efficient and rapid selective adsorption capacity for cationic dyes. The experimental adsorption capacity (qex) of P1 reaches a value of up to 789.2 mg/g at 298 K for the crystal violet dye, which is the highest among those of various adsorbents. The calculated models are first used to reveal the structure-property relationship of the cyclic host to different guest dyes. The results further confirmed the host MOF structure of P1.

9.
BMC Ophthalmol ; 24(1): 190, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658861

RESUMEN

BACKGROUND: Ciliary body tumor is extremely rare and treatment is challenging. The aim of this study is to present our experience in treating this rare entity, especially large tumors with more than 5 clock hours of involvement, and to evaluate the surgical outcomes and complications of local resection via partial lamellar sclerouvectomy in four cases of ciliary body tumors in China. METHODS: Four patients with ciliary body tumors underwent partial lamellar sclerouvectomy between October 2019 and April 2023 in Shanghai General Hospital, China. Tumor features, histopathologic findings, complications, visual acuity, and surgical outcomes were reviewed at a mean follow-up of 20.8 months. RESULTS: Four patients with a mean age of 31.8 years were included in this study. The histopathological diagnosis was adenoma of non-pigmented ciliary epithelium (ANPCE), schwannoma, and multiple ciliary body pigment epithelial cysts. The mean largest tumor base diameter was 6.00 mm (range: 2.00-10.00) and the mean tumor thickness was 3.50 mm (range: 2.00-5.00). Preoperative complications included cataract in 3 (75%) eyes, lens dislocation in 2 (50%), and secondary glaucoma in 1 (25%). Temporary ocular hypotonia was observed in one case and no other postoperative complications were observed. At a mean follow-up of 20.8 months, the best corrected visual acuity increased in 3 eyes and was stable in 1 eye. Tumor recurrence was absent in all eyes. All patients were alive at the end of follow-up. CONCLUSIONS: Local tumor resection via PLSU is useful in the treatment of ciliary body tumors, including large tumors occupying more than five clock hours of pars plicata. Surgery-related complications were manageable with adequate preoperative assessment and careful operation during surgery.


Asunto(s)
Cuerpo Ciliar , Esclerótica , Neoplasias de la Úvea , Agudeza Visual , Adulto , Humanos , Cuerpo Ciliar/cirugía , Cuerpo Ciliar/patología , Estudios de Seguimiento , Procedimientos Quirúrgicos Oftalmológicos/métodos , Estudios Retrospectivos , Esclerótica/cirugía , Esclerótica/patología , Neoplasias de la Úvea/cirugía , Neoplasias de la Úvea/diagnóstico , Agudeza Visual/fisiología
10.
BMC Health Serv Res ; 24(1): 23, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-38178099

RESUMEN

OBJECTIVE: The outbreak of the COVID-19 pandemic has drawn attention from all sectors of society to the level of public health services. This study aims to investigate the level of public health service supply in the four major regions of Guangdong Province, providing a basis for optimizing health resource allocation. METHODS: This article uses the entropy method and panel data of 21 prefecture-level cities in Guangdong Province from 2005 to 2021 to construct the evaluation index system of public health service supply and calculate its supply index. On this basis, the standard deviation ellipse method, kernel density estimation, and Markov chain are used to analyze the spatiotemporal evolution trend of the public health service supply level in Guangdong Province. The Dagum Gini coefficient and panel regression model are further used to analyze the relative differences and the key influencing factors of difference formation. Finally, the threshold effect model is used to explore the action mechanism of the key factors. RESULTS: Overall, the level of public health service supply in Guangdong Province is on an upward trend. Among them, polarization and gradient effects are observed in the Pearl River Delta and Eastern Guangdong regions; the balance of public health service supply in Western Guangdong and Northern Mountainous areas has improved. During the observation period, the level of public health services in Guangdong Province shifted towards a higher level with a smaller probability of leapfrogging transition, and regions with a high level of supply demonstrated a positive spillover effect. The overall difference, intra-regional difference and inter-regional difference in the level of public health service supply in Guangdong Province during the observation period showed different evolutionary trends, and spatial differences still exist. These differences are more significantly positively affected by factors such as the level of regional economic development, the degree of fiscal decentralization, and the urbanization rate. Under different economic development threshold values, the degree of fiscal decentralization and urbanization rate both have a double threshold effect on the role of public health service supply level. CONCLUSION: The overall level of public health service supply in Guangdong Province has improved, but spatial differences still exist. Key factors influencing these differences include the level of regional economic development, the degree of fiscal decentralization, and the urbanization rate, all of which exhibit threshold effects. It is suggested that, in view of the actual situation of each region, efforts should be made to build and maintain their own advantages, enhance the spatial linkage of public health service supply, and consider the threshold effects of key factors in order to optimize the allocation of health resources.


Asunto(s)
Pandemias , Urbanización , Humanos , China/epidemiología , Ciudades , Servicios de Salud
11.
Nano Lett ; 23(6): 2370-2378, 2023 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-36897606

RESUMEN

Transferring structural information from amino acid sequence to macroscale assembly is a challenging approach for designing protein quaternary structure. However, the pathway by which the slight variations in sequence result in a global perturbation effect on the assembled structure is unknown. Herein, we design two synthetic peptides, QNL-His and QNL-Arg, with one amino acid substitution and use scanning tunneling microscopy (STM) to image individual peptides in the assembled state. The submolecular resolution of STM enables us to determine the folding structure and ß-sheet supramolecular organization of peptides. QNL-His and QNL-Arg differ in their ß-strand length distribution in pleated ß-sheet association. These structural variations lead to distinguishable outcomes in their ß-sheet assembled fibrils and phase transitions. The comparison of QNL-His versus QNL-Arg structures and macroscopic properties unveils the role of assembly to amplify the structural variations associated with a single-site mutation from a single-molecule scale to a macroscopic scale.


Asunto(s)
Microscopía de Túnel de Rastreo , Péptidos , Conformación Proteica en Lámina beta , Estructura Secundaria de Proteína , Péptidos/química , Secuencia de Aminoácidos
12.
Int J Mol Sci ; 25(6)2024 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-38542381

RESUMEN

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aß) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aß1-42 and Aß plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aß1-42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aß plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aß levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models.


Asunto(s)
Enfermedad de Alzheimer , Ácidos Cafeicos , Molécula L1 de Adhesión de Célula Nerviosa , Neuroblastoma , Enfermedades Neurodegenerativas , Succinatos , Humanos , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ratones Transgénicos , Modelos Animales de Enfermedad , Ácido Aspártico Endopeptidasas/metabolismo , Péptidos beta-Amiloides/metabolismo
13.
Angew Chem Int Ed Engl ; 63(17): e202318568, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38433368

RESUMEN

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML.


Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/uso terapéutico , Línea Celular Tumoral , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Proteolisis , Proteína p53 Supresora de Tumor/metabolismo
14.
Opt Lett ; 48(3): 566-569, 2023 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-36723532

RESUMEN

We experimentally demonstrate to drive domain growth in lithium niobate crystal by using a focused infrared femtosecond laser without relative displacement or any additional treatment. The physical process has four stages: modified domain generation; thermoelectric field formation; domain inversion; and domain growth. The length of domain growth depends on drive energy (pulse energy) and drive time (number of pulses), up to 155 µm. We use this approach to rapidly fabricate two-dimensional period-inverted domain structures and perform frequency-doubling conversion based on quasi-phase-matching. Laser-driven domain growth delivers an efficient manufacturing route for tailored functional materials.

15.
Cell Biol Int ; 47(9): 1614-1626, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37332141

RESUMEN

Uveitis is a major cause of vision impairment worldwide. Current treatments have limited effectiveness but severe complications. Mannose binding lectin (MBL) is an important protein of the innate immune system that binds to TLR4 and suppresses LPS-induced inflammatory cytokine secretion. MBL-mediated inhibition of inflammation via the TLR4 pathway and MBL-derived peptides might be a potential therapeutics. In this study, we designed a novel MBL-derived peptide, WP-17, targeting TLR4. Bioinformatics analysis was conducted for the sequence, structure and biological properties of WP-17. The binding of WP-17 to THP-1 cells was analyzed using flow cytometry. Signaling molecules were analyzed by western blotting, and activation of NF-κB was measured by immunofluorescence-histochemical analysis. Effects of WP-17 were studied in vitro using LPS-stimulated THP-1 cells and in vivo in endotoxin-induced uveitis (EIU). Our results showed that WP-17 could bind to TLR4 expressed on macrophages, thus downregulating the expression levels of MyD88, IRAK-4, and TRAF-6, and inhibiting the downstream NF-kB signaling pathway and LPS-induced expression of TNF-α and IL-6 in THP-1 cells. Moreover, in EIU rats, intravitreal pretreatment with WP-17 demonstrated significant inhibitory effects on ocular inflammation, attenuating the clinical and histopathological manifestations of uveitis, reducing protein leakage and cell infiltration into the aqueous humor, and suppressing TNF-α and IL-6 production in ocular tissues. In summary, our study provides the first evidence of a novel MBL-derived peptide that suppressed activation of the NF-кB pathway by targeting TLR4. The peptide effectively inhibited rat uveitis and may be a promising candidate for the management of ocular inflammatory diseases.


Asunto(s)
FN-kappa B , Uveítis , Ratas , Animales , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Inflamación/tratamiento farmacológico , Inflamación/patología , Uveítis/inducido químicamente , Uveítis/tratamiento farmacológico , Uveítis/patología , Péptidos/farmacología , Péptidos/uso terapéutico , Lectinas de Unión a Manosa/metabolismo , Lectinas de Unión a Manosa/farmacología , Lectinas de Unión a Manosa/uso terapéutico
16.
Org Biomol Chem ; 21(20): 4191-4194, 2023 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-37132390

RESUMEN

Fused furans are commonly found units in natural products and medicinal molecules, and methods for their introduction are of fundamental importance. Here we report one-pot cycloadditions of ethynyl indoloxazolidones with 1,3-cyclohexanediones enabled by copper catalysis, leading to a series of functionalized furan derivatives in good yields. This method features mild reaction conditions, high efficiency, and wide substrate scope.

17.
Bioorg Med Chem ; 81: 117202, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36804726

RESUMEN

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutagénesis Insercional , Receptores ErbB , Inhibidores de Proteínas Quinasas/química , Mutación , Exones
18.
Brain Topogr ; 36(3): 350-370, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37046041

RESUMEN

Magnetoencephalography (MEG) is a noninvasive functional neuroimaging modality but highly susceptible to environmental interference. Signal space separation (SSS) is a method for improving the SNR to separate the MEG signals from external interference. The origin and truncation values of SSS significantly affect the SSS performance. The origin value fluctuates with respect to the helmet array, and determining the truncation values using the traversal method is time-consuming; thus, this method is inappropriate for optically pumped magnetometer (OPM) systems with flexible array designs. Herein, an automatic optimization method for the SSS parameters is proposed. Virtual sources are set inside and outside the brain to simulate the signals of interest and interference, respectively, via forward model, with the sensor array as prior information. The objective function is determined as the error between the signals from simulated sources inside the brain and the SSS reconstructed signals; thus, the optimized parameters are solved inversely by minimizing the objective function. To validate the proposed method, a simulation analysis and MEG auditory-evoked experiments were conducted. For an OPM sensor array, this method can precisely determine the optimized origin and truncation values of the SSS simultaneously, and the auditory-evoked component, for example, N100, can be accurately located in the temporal cortex. The proposed optimization procedure outperforms the traditional method with regard to the computation time and accuracy, simplifying the SSS process in signal preprocessing and enhancing the performance of SSS denoising.


Asunto(s)
Encéfalo , Magnetoencefalografía , Humanos , Magnetoencefalografía/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Mapeo Encefálico/métodos , Simulación por Computador , Neuroimagen Funcional
19.
Surg Endosc ; 37(7): 5065-5076, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36879165

RESUMEN

BACKGROUND: Anastomotic leakage and postoperative pancreatic fistula (POPF) may occur after pancreatic head resection, also in the setting of pancreato-gastric reconstruction. For adequate complication management, a variety of non-standardized treatments are available. Still, data on clinical evaluation of endoscopic methods remain scarce. Based on our interdisciplinary experience on endoscopic treatment of retro-gastric fluid collections after left-sided pancreatectomies, we developed an innovative endoscopic concept with internal peri-anastomotic stent placement for patients with anastomotic leakage and/or peri-anastomotic fluid collection. METHODS: Over the period of 6 years (2015-2020) we retrospectively evaluated 531 patients after pancreatic head resections at the Department of Surgery, Charité-Unversitätsmedizin Berlin. Of these, 403 received reconstruction via pancreatogastrostomy. We identified 110 patients (27.3%) with anastomotic leakage and/or peri-anastomotic fluid collection and could define four treatment groups which received either conservative treatment (C), percutaneous drainage (PD), endoscopic drainage (ED), and/or re-operation (OP). Patients were grouped in a step-up approach for descriptive analyses and in a stratified, decision-based algorithm for comparative analyses. The study's primary endpoints were hospitalization (length of hospital stay) and clinical success (treatment success rate, primary/secondary resolution). RESULTS: We characterized an institutional, post-operative cohort with heterogenous complication management following pancreato-gastric reconstruction. The majority of patients needed interventional treatments (n = 92, 83.6%). Of these, close to one-third (n = 32, 29.1%) were treated with endoscopy-guided, peri-anastomotic pigtail stents for internal drainage as either primary, secondary and/or tertiary treatment modality. Following a decision-based algorithm, we could discriminate superior primary-(77,8% vs 53.7%) and secondary success rates (85.7% vs 68.4%) as well as earlier primary resolutions (11.4 days, 95%CI (5.75-17.13) vs 37.4 days, 95%CI (27.2-47.5)] in patients receiving an endoscopic compared to percutaneous management. CONCLUSION: This study underscores the importance of endoscopy-guided approaches for adequate treatment of anastomotic leakage and/or peri-anastomotic fluid collections after pancreatoduodenectomy. We herein report a novel, interdisciplinary concept for internal drainage in the setting of pancreato-gastric reconstruction.


Asunto(s)
Fuga Anastomótica , Páncreas , Humanos , Fuga Anastomótica/etiología , Fuga Anastomótica/cirugía , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Endoscopía Gastrointestinal/métodos , Drenaje/métodos , Resultado del Tratamiento , Stents
20.
BMC Public Health ; 23(1): 1089, 2023 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-37280569

RESUMEN

BACKGROUND: Various nonpharmaceutical interventions (NPIs) against COVID-19 continue to have an impact on socioeconomic and population behaviour patterns. However, the effect of NPIs on notifiable infectious diseases remains inconclusive due to the variability of the disease spectrum, high-incidence endemic diseases and environmental factors across different geographical regions. Thus, it is of public health interest to explore the influence of NPIs on notifiable infectious diseases in Yinchuan, Northwest China. METHODS: Based on data on notifiable infectious diseases (NIDs), air pollutants, meteorological data, and the number of health institutional personnel in Yinchuan, we first fitted dynamic regression time series models to the incidence of NIDs from 2013 to 2019 and then estimated the incidence for 2020. Then, we compared the projected time series data with the observed incidence of NIDs in 2020. We calculated the relative reduction in NIDs at different emergency response levels in 2020 to identify the impacts of NIPs on NIDs in Yinchuan. RESULTS: A total of 15,711 cases of NIDs were reported in Yinchuan in 2020, which was 42.59% lower than the average annual number of cases from 2013 to 2019. Natural focal diseases and vector-borne infectious diseases showed an increasing trend, as the observed incidence in 2020 was 46.86% higher than the estimated cases. The observed number of cases changed in respiratory infectious diseases, intestinal infectious diseases and sexually transmitted or bloodborne diseases were 65.27%, 58.45% and 35.01% higher than the expected number, respectively. The NIDs with the highest reductions in each subgroup were hand, foot, and mouth disease (5854 cases), infectious diarrhoea (2157 cases) and scarlet fever (832 cases), respectively. In addition, it was also found that the expected relative reduction in NIDs in 2020 showed a decline across different emergency response levels, as the relative reduction dropped from 65.65% (95% CI: -65.86%, 80.84%) during the level 1 response to 52.72% (95% CI: 20.84%, 66.30%) during the level 3 response. CONCLUSIONS: The widespread implementation of NPIs in 2020 may have had significant inhibitory effects on the incidence of respiratory infectious diseases, intestinal infectious diseases and sexually transmitted or bloodborne diseases. The relative reduction in NIDs during different emergency response levels in 2020 showed a declining trend as the response level changed from level 1 to level 3. These results can serve as essential guidance for policy-makers and stakeholders to take specific actions to control infectious diseases and protect vulnerable populations in the future.


Asunto(s)
COVID-19 , Enfermedades Transmisibles , Enfermedades Intestinales , Humanos , Factores de Tiempo , COVID-19/epidemiología , Enfermedades Transmisibles/epidemiología , China/epidemiología , Incidencia
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