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1.
Anal Chim Acta ; 1238: 340609, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36464444

RESUMO

In this work, a novel label-free and signal-off electrochemical biosensor based on efficient target-trigger T-structure recycling with dual strand displacement amplification (T-DSDA) was constructed for sensitive detection of miRNA-155 that related to cardiovascular diseases. Compared with traditional SDA, the proposed strategy not only accomplished simple polymerization and shearing of dsDNA without continuous consumption of temple DNA, but also ingeniously designed two analogous sequences that produced double cleavage sites, thereby obtaining extensive output DNA for further cleaving Y-structure assembled on electrode with significantly improved target conversion efficiency. Since the redox probe methylene blue (MB) attach to Y-structure via electrostatic interaction and tessellation, an obviously decreased current with a typical signal-off mode could be acquired for sensing miRNA-155 in the assistant of DNAzyme cleavage recycling. As a result, the electrochemical biosensor realized the rapid and sensitive detection of miRNA-155 with a low detection limit down to 166.7 fM. In addition, the biosensor displayed a strong anti-interference ability in bovine whole blood, and thus was expected to be applied to detect blood samples of various miRNA-155 related diseases in clinical diagnosis.


Assuntos
Técnicas Biossensoriais , DNA Catalítico , MicroRNAs , Animais , Bovinos , Eletrodos , Azul de Metileno , MicroRNAs/genética
2.
Sci Total Environ ; 858(Pt 1): 159753, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341850

RESUMO

Manganese (Mn) overexposure induces learning and memory impairments in mice by disrupting the functions of synapses and synaptic vesicles (SVs) in the hippocampus, which is associated with α-synuclein (α-Syn) overexpression. Rab26-dependent autophagy is a key signaling step required for impaired SV clearance; however, it is unclear whether Mn-induced α-Syn overexpression is linked to dysregulated Rab26-dependent autophagy in presynaptic neurons. In this study, we developed manganism models in male C57BL/6 mice and hippocampal primary neurons to observe the associations between Mn-induced α-Syn overexpression and impaired SV accumulation. The results of the in vivo experiments showed that 100 and 200 µmol/kg Mn exposure significantly impaired memory and synaptic plasticity in the mice, which was related to the accumulation of impaired SVs in the hippocampus. Consistent with the in vivo outcomes, the level of in vitro injured SVs in the 50 and 100 µmol/L Mn-exposed neuron group were higher than that in the control group. Moreover, 100 µmol/L Mn suppressed the initiation of Rab26-dependent autophagy at the synapse. Then, we transfected neurons with LV-α-Syn short hairpin RNA (shRNA) and exposed the neurons to Mn for an additional 24 h. Surprisingly, the area of colocalization between Rab26 and Atg16L1 and the expression level of LC3II-positive SVs were both higher in Mn-exposed LV-α-Syn shRNA-transfected neurons than those in Mn-treated normal or Mn-treated LV-scrambled shRNA-transfected neurons. Thus, Mn-induced α-Syn overexpression was responsible for the dysregulation of Rab26-dependent autophagy, thereby promoting the accumulation of injured SVs, and causing synaptotoxicity and cognitive and memory deficits in mice.


Assuntos
Vesículas Sinápticas , alfa-Sinucleína , Animais , Masculino , Camundongos , Vesículas Sinápticas/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Manganês/toxicidade , Manganês/metabolismo , RNA Interferente Pequeno/metabolismo , Camundongos Endogâmicos C57BL , Neurônios , Hipocampo/metabolismo , Autofagia
3.
Artigo em Inglês | MEDLINE | ID: mdl-36244570

RESUMO

Aquatic water with carbonate alkalinity presents a survival challenge to aquatic animals. As an economically important crab, large quantities of Eriocheir sinensis are cultured in carbonate-type saline-alkali ponds, while the toxic effect on E. sinensis from carbonate alkalinity is still unclear. In this study, untargeted liquid chromatography-mass spectrometry metabolomics was performed to investigate the metabolic change caused by culture alkalinity, and confirmed distinct physiological response under gradient alkalinities. There were 39 differential metabolites obtained in the low-alkalinity group (4.35 mmol/L) versus control group, and "arachidonic acid metabolism" was enriched as a core response pathway. 93 differential metabolites were identified in the high-alkalinity group (17.43 mmol/L) versus control group, and a complex response net was manifested through integrated analysis, building by "steroid hormone biosynthesis", "phenylalanine, tyrosine and tryptophan biosynthesis", "phosphonate and phosphinate metabolism", "phenylalanine metabolism", "mineral absorption", "purine metabolism" and "carbon metabolism". This indicated the mobilization of energy reserves and the suppression of protein and amino acid catabolism were manifested in E. sinensis gills to defense high alkalinity stress. In addition, the persistently regulation of key metabolites under various alkalinity, including diuretic compound "spironolactone" and the antiphlogistic compound "LXB4", suggested anti-inflammatory action and excretion regulation were initiated to defend the stress.


Assuntos
Braquiúros , Animais , Brânquias/metabolismo , Carbonatos/toxicidade , Metabolômica , Fenilalanina/metabolismo
4.
Gene ; 851: 146982, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36270456

RESUMO

The phytohormone auxin plays a pivotal role in regulating plant growth, development, and abiotic stress responses by promptly controlling the expression of auxin response genes. The Gretchen Hagen3 (GH3) genes are a major early auxin response gene family that contribute to auxin homeostasis by conjugating excess auxins to amino acids. To our knowledge, a genome-wide investigation of the GH3 genes in alfalfa has never been reported. Here, we present a comprehensive bioinformatics analysis of the MsGH3 gene family, including chromosomal locations, phylogenetic relationships, gene structures, conserved motifs and Gene Ontology annotation. Interestingly, the analysis revealed 31 MsGH3 genes in the alfalfa genome. These genes were classified phylogenetically into the GH3-I, GH3-II, and GH3-III subgroups. Additionally, the data analysis showed that most MsGH3 genes are tissue specific and responsive to environmental stress-related hormones. Furthermore, the analysis of cis elements and potential biological functions revealed that the MsGH3 genes play potential roles in various stress responses. Notably, qRT-PCR results following exposure to high temperature, drought, and salt treatments demonstrated that most of the MsGH3 family genes, especially MsGH3-12, MsGH3-13, and MsGH3-15, play important roles in stress responses. These findings provide invaluable insight for future practical analyses and genetic improvement of alfalfa abiotic stress tolerance.


Assuntos
Regulação da Expressão Gênica de Plantas , Medicago sativa , Medicago sativa/genética , Medicago sativa/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia , Ácidos Indolacéticos/metabolismo , Estresse Fisiológico/genética , Família Multigênica
5.
Environ Pollut ; 316(Pt 1): 120613, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36351484

RESUMO

The percolation-degradation process of soluble domestic pollution is very important for the evolution of soil properties and the formation of contaminated sites. The main objective of this study is to investigate the influence of glucose seepage-degradation on the permeability of clay through an indoor percolation test in combination with thermogravimetric measurement with glucose as a representative domestic contaminant soluble sugar. We can conclude that the permeability of clay was significantly impacted by the seepage-degradation of soluble sugar. With a focus on the role of soluble sugars in domestic source pollutants on clay, the formation and evolution of the domestic source contaminated soil site went through three main stages: "generation of domestic source contaminated liquid & formation of S-C zone", "contraction of S-C zone & formation of E-C zone and C zone", and "disappearance of S-C zone & contraction of E-C zone and C zone". The clay permeability decreased, the migration range shrinked, and the pollution level of the clay near the source of the contaminants increased with increasing soluble sugar solution concentration.

6.
Environ Pollut ; 316(Pt 2): 120670, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36395908

RESUMO

Color vision, initiated from cone cells, is vitally essential for identifying environmental information in vertebrate. Although the retinotoxicity of bisphenol S (BPS) has been reported, data on the influence of BPS treatment on cone cells are scarce. In the present study, transgenic zebrafish (Danio rerio) labeling red and ultraviolet (UV) cones were exposed to BPS (0, 1, 10, and 100 µg/L) during the early stages of retinal development, to elucidate the mechanism underlying its retinal cone toxicity of BPS. The results showed that 10 and 100 µg/L BPS induced oxidative DNA damage, structural damage (decreased number of ribbon synapses), mosaic patterning disorder, and altered expression of genes involved in the phototransduction pathway in red and UV cones. Furthermore, BPS exposure also caused abnormal development of key neurons (retinal ganglion cells, optic nerve, and hypothalamus), responsible for transmitting the light-electrical signal to brain, and thereby resulted in inhibition of light-electrical signal transduction, finally diminishing the spectral sensitivity of zebrafish larvae to long- and short-type light signal at 5 day post fertilization. This study highlights the cone-toxicity of environmental relevant concentrations of BPS, and clarifies the mechanism of color vision impairment induced by BPS at the cellular level, updating the understanding of visual behavior driven by environmental factors.


Assuntos
Sulfonas , Peixe-Zebra , Animais , Larva , Fenóis/toxicidade
7.
J Hazard Mater ; 442: 130018, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36155301

RESUMO

The expansion of large-scale nuclear power causes a substantial volume of radioactive wastewater containing uranium to be released into the environment. Because of uranium's toxicity and bioaccumulation, it is critical to develop the efficient and sustainable materials for selective removal of uranium (VI). Herein, a regenerable anti-biofouling nano zero-valent iron doped porphyrinic zirconium metal-organic framework (NZVI@PCN-224) heterojunction system was successfully fabricated. Due to the Schottky-junction effect at the NZVI/MOF interface, the NZVI nanomaterial immobilized on PCN-224 could improve interfacial electron transfer and separation efficiency, and enhance entire reduction of highly soluble U(VI) to less soluble U(IV), involving photocatalytic reduction and chemical reduction. Meanwhile, the photocatalytic effect also prompts the NZVI@PCN-224 to produce more biotoxic reactive oxygen species (ROS), resulting in high anti-microbial and anti-algae activities. Under dark conditions, NZVI@PCN-224 with a large specific surface area could provide sufficient oxo atoms as the uranium binding sites and show the highest uranium-adsorbing capability of 57.94 mg/g at pH 4.0. After eight adsorption-desorption cycles, NZVI@PCN-224 still retained a high uranium adsorption capacity of 47.98 mg/g and elimination efficiency (91.72%). This sorption/reduction/anti-biofouling synergistic strategy of combining chelation, chemical reduction and photocatalytic performance inspires new insights for highly efficient treatment of liquid radioactive waste.


Assuntos
Estruturas Metalorgânicas , Resíduos Radioativos , Urânio , Poluentes Químicos da Água , Ferro/química , Urânio/química , Águas Residuárias , Resíduos Radioativos/prevenção & controle , Espécies Reativas de Oxigênio , Carbonitrila de Pregnenolona , Zircônio , Adsorção , Poluentes Químicos da Água/química
8.
Food Chem ; 400: 134050, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36058042

RESUMO

The protein-bound anthocyanin complexes are naturally existed in food systems by their spontaneous interaction. In this study, the interaction mechanism of homological proteins (p-PSP) and anthocyanins (FAC-PSP) was investigated to explore the binding characteristic of native protein-bound anthocyanins from purple sweet potato (p-BAC-PSP). The structural characterization, stability and anti-ultraviolet property of p-BAC-PSP were also evaluated. Results revealed that hydrophobic interaction is dominant binding force for forming p-BAC-PSP. The binding resulted in protein secondary structure changes with more ß-sheet and lower ß-turn, random coil structures. Fluorescence spectroscopy demonstrated that FAC-PSP quenched p-PSP fluorescence in a combination of static and dynamic mode (static dominant) with a binding constant of 105 L/mol reflecting strong affinity of FAC-PSP to p-PSP. Moreover, the complex form exhibited better protective effects on anthocyanins for pH, light, thermal stabilities and higher anti-ultraviolet activity. These findings further expanded the application of anthocyanins as stable, functional food and cosmetic ingredients.


Assuntos
Ipomoea batatas , Antocianinas/química , Ipomoea batatas/química , Extratos Vegetais/química
9.
J Clin Transl Hepatol ; 11(1): 118-129, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36406317

RESUMO

Background and Aims: Patients with persistent positive hepatitis B surface antigen (HBsAg), even with a low HBV-DNA load, have a higher risk of hepatocellular carcinoma (HCC) than those without HBV infection. Given that tumor stemness has a critical role in the occurrence and maintenance of neoplasms, this study aimed to explore whether HBsAg affects biological function and stemness of HCC by regulating microRNA, and to explore underlying mechanisms. Methods: We screened out miR-203a, the most significant down-regulated microRNA in the microarray analysis of HBsAg-positive samples and focused on that miRNA in the ensuing study. In vitro and in vivo functional experiments were performed to assess its regulatory function. The effect of miR-203a on stemness and the possible correlation with BMI1 were analyzed in this study. Results: MiR-203a was significantly down-regulated in HBsAg-positive HCC with the sharpest decrease shown in microarray analysis. The negative correlation between miR-203a and HBsAg expression was confirmed by quantitative real-time PCR after stimulation or overexpression/knockdown of HBsAg in cells. We demonstrated the function of miR-203a in inhibiting HCC cell proliferation, migration, clonogenic capacity, and tumor development in vivo. Furthermore, the overexpression of miR-203a remarkably increases the sensitivity of tumor cells to 5-FU treatment and decreases the proportion of HCC cells with stem markers. In concordance with our study, the survival analysis of both The Cancer Genome Atlas database and samples in our center indicated a worse prognosis in patients with low level of miR-203a. We also found that BMI1, a gene maintains the self-renewal capacity of stem cells, showed a significant negative correlation with miR-203a in HCC specimen (p<0.001). Similarly, opposite BMI1 changes after overexpression/knockdown of miR-203a were also confirmed in vitro. Dual luciferase reporting assay suggested that miR-203a may regulate BMI1 expression by direct binding. Conclusions: HBsAg may promote the development of HCC and tumor stemness by inhibiting miR-203a, resulting in poor prognosis. miR-203a may serve as a crucial treatment target in HBsAg-positive HCC. More explicit mechanistic studies and animal experiments need to be conducted as a next step.

10.
Cancer Lett ; 553: 215993, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36328162

RESUMO

Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal and widespread malignancies in China. Exosomes, a subset of tiny extracellular vesicles manufactured by all cells and present in all body fluids, contribute to intercellular communication and have become a focus of the search for new therapeutic strategies for cancer. A number of global analyses of exosome-mediated functions and regulatory mechanism in malignant diseases have recently been reported. There is extensive evidence that exosomes can be used as diagnostic and prognostic markers for cancer. However, our understanding of their clinical value and mechanisms of action in ESCC is still limited and has not been systematically reviewed. Here, we review current research specifically focused on the functions and mechanisms of action of ESCC tumor-derived exosomes and non-ESCC-derived exosomes in ESCC progression and describe opportunities and challenges in the clinical translation of exosomes.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Exossomos , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Exossomos/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , China , Linhagem Celular Tumoral
11.
Food Chem ; 401: 134081, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36113214

RESUMO

To address the limitation of strong hydrophilicity of edible films, starch/gelatin (S/G) films incorporated with natural waxes (beeswax (BW), candelilla wax (CL), and carnauba wax (CB)) were fabricated by extrusion blowing. Rheological analysis demonstrated that the incorporation of natural waxes reduced storage modulus and complex viscosity of S/G blends. BW and CL weakened molecular interactions among film components, whereas CB did not. CB exhibited the strongest crystalline behavior after film formation. The degree of starch gelatinization and water vapor barrier property of films depended on wax type. The presence of waxes increased the water resistance and surface hydrophobicity of the films. However, CL and BW addition decreased the tensile strength of films. The highest water contact angle (102.6°), strongest thermal stability, and lowest water vapor permeability were found in S/G-BW film, which could be the optimal choice to produce highly hydrophobic edible films.


Assuntos
Filmes Comestíveis , Amido , Amido/química , Gelatina/química , Vapor , Ceras/química , Resistência à Tração , Permeabilidade
12.
J Colloid Interface Sci ; 630(Pt B): 86-98, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36327742

RESUMO

Fe based metal organic framework (MOF) materials are being extensively investigated as a precursor sample for engineering carbon supported iron containing nanoparticles composites. Rational design and engineering Fe-containing MOFs with optimized structures using economic and eco-friendly methods is a challenging task. In this work, 1,3,5-benzenetricarboxylic acid (C9H6O6, trimesic acid, H3BTC) and metal Fe are employed to synthesize a MOF sample Fe-BTC in a mild hydrothermal condition. Moreover, with the addition of a small quantity of graphene oxide (GO) as dispersant, a redox coprecipitation reaction has taken place where small Fe-BTC domains well dispersed by reduced graphene oxide (RGO). The Fe-BTC/RGO intermediate sample is finally converted to the hierarchical Fe3O4@C/RGO composite, which delivers an ultrahigh specific capacity of 1262.61 mAh·g-1 at 200 mA·g-1 after 150 cycles and a superior reversible capacity of 910.65 mAh·g-1 at 1000 mA·g-1 after 300 cycles in half cells. The full cell performance for the Fe3O4@C/RGO composite have been studied. It is also revealed that the improved structural stability, high pseudocapacitive contribution and enhanced lithium-ion and electron transportation conditions jointly guarantee the outstanding lithium-ion storage performances for the Fe3O4@C/RGO composite over long-time cycling. The synthesized samples have good potential for wider application.

13.
J Chem Phys ; 157(20): 204201, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36456225

RESUMO

As one of the popular coherent Raman scattering techniques, stimulated Raman scattering (SRS) has made significant progress in recent years, especially in label-free biological imaging. Polarization provides an additional degree of freedom to manipulate the SRS process. In previous studies, only linearly polarized SRS was fully investigated, in which both pump and Stokes laser fields are linearly polarized. Here, we theoretically analyzed the SRS process excited by two circularly polarized laser fields and then experimentally demonstrated it by taking a spherical symmetric CH4 molecule as a model system. The experimental results are in good agreement with the theoretical ones. It is shown that circularly polarized SRS (CP-SRS) has unique characteristics different from linear polarization. When the handedness of circular polarization states of two laser fields is the same, CP-SRS further suppresses the depolarized vibrational band while keeping the polarized band almost unaffected. On the other hand, when the handedness is opposite, CP-SRS enhances the depolarized band while suppressing the polarized band. Therefore, the CP-SRS not only allows us to resolve the symmetry of vibrational modes but also can enhance vibrational contrast based on symmetry selectivity by suppressing or enhancing the signal from a specific vibrational mode. These results will have potential applications in improving chemical selectivity and imaging contrast as well as spectral resolution SRS microscopy. In addition, the CP-SRS has the ability to determine the depolarization ratio ρ and identify the overlapping Raman bands.


Assuntos
Análise Espectral Raman , Vibração , Microscopia , Modelos Biológicos
14.
Arch Med Sci ; 18(6): 1626-1637, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457959

RESUMO

Introduction: The function of the C6orf120 gene, which encodes an N-glycosylated protein, remains unknown. The study was performed to characterize the utility of the C6orf120 gene in carbon tetrachloride-induced acute liver injury and to elucidate the potential underlying mechanisms by establishing a C6orf120 gene-knockout (C6orf120-/-) rat model. Material and methods: C6orf120-/- and wild-type (WT) rats were intraperitoneally administered with CCl4 (1 : 1 v/v in olive oil, 2 µl/g). Rats were sacrificed 24 h after CCl4 administration. Liver tissues were collected for H&E, IHC, qRT-PCR, and Western blot analysis. Results: C6orf120 gene deficiency may be vulnerable to CCl4-induced acute liver injury in rats as indicated by the high levels of alanine aminotransferase (WT: 388.7 ±55.96 vs. C6orf120-/-: 915.9 ±118.8, p < 0.001) and greater degree of pathological damage. Quantitative reverse transcription polymerase chain reaction showed that the mRNA levels of inflammation-associated cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, in liver tissues were increased in C6orf120-/- rats compared with those in WT rats. Moreover, western blot showed that the protein expression of cytokines nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, nuclear factor-κB, c-Jun N-terminal kinases, and Bax were increased in C6orf120-/- rats compared with those in WT rats. Conclusions: C6orf120-/- rats were susceptible to CCl4-induced liver injury, which may be related to NLRP3 inflammasome and JNK signaling pathway activation.

15.
Biosens Bioelectron ; 222: 114932, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36462429

RESUMO

The localization of isothermal amplification systems has elicited extensive attention due to the enhanced reaction kinetics when detecting ultra-trace small-molecule nucleic acids. Therefore, the seek for an appropriate localization cargo of spatially confined reactions is urgent. Herein, we have developed a novel approach to localize the catalytic hairpin assembly (CHA) system into the DNA tile self-assembly nanostructure. Thanks to the precise programming and robust probe loading capacity, this strategy achieved a 2.3 × 105-fold higher local reaction concentration than a classical CHA system with enhanced reaction kinetics in theory. From the experimental results, this strategy could reach the reaction plateau faster and get access to a magnified effect of 1.57-6.99 times higher in the linear range of microRNA (miRNA) than the simple CHA system. Meanwhile, this strategy satisfied the demand for the one-step detection of miRNA in cell lysates at room temperature with good sensitivity and specificity. These features indicated its excellent potential for ultra-trace molecule detection in clinical diagnosis and provided new insights into the field of bioassays based on DNA tile self-assembly nanotechnology.

16.
Front Psychol ; 13: 1010162, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36467181

RESUMO

The impact of personal risk caused by controlling shareholders' equity pledges on the company's debt policy is an issue worth exploring. Using Chinese A-share listed companies from 2006 to 2020, this paper studies the impact of ultimate owner equity pledges on firm debt size and debt maturity structure and explores the mechanism of ultimate owner personal leverage on firms. The results show that the increase in ultimate owner stock pledges leads to higher financial leverage and a longer debt maturity structure for the company. In addition, the study reveals that the high personal leverage of the ultimate owner of the pledged equity is an influential mechanism driving the transfer of personal risk to the firm. In particular, even if a company's actual debt ratio is higher than its target debt ratio, equity pledges can prompt listed companies to increase their debt ratios and debt maturities, causing them to take on excessive debt risk and transfer the risk to creditors. It follows that the tunneling effect is a driving force of equity pledging and corporate debt policies. These results remain robust after the robustness test and endogenous test. The conclusions of this paper not only emphasize the impact of shareholders' personal risk on the firm but also provide a reference for investors' perception of firm risk.

17.
J Med Chem ; 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36469401

RESUMO

Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.

18.
Front Immunol ; 13: 1052542, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466925

RESUMO

Background: Currently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC. Methods: Of 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors. Results: After adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062). Conclusion: For patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/terapia , Terapia Neoadjuvante , Neoplasias Esofágicas/terapia , Imunoterapia/efeitos adversos , Complicações Pós-Operatórias , Resultado do Tratamento
19.
Proc Natl Acad Sci U S A ; 119(50): e2122494119, 2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36469777

RESUMO

Physical interfaces widely exist in nature and engineering. Although the formation of passive interfaces is well elucidated, the physical principles governing active interfaces remain largely unknown. Here, we combine simulation, theory, and cell-based experiment to investigate the evolution of an active-active interface. We adopt a biphasic framework of active nematic liquid crystals. We find that long-lived topological defects mechanically energized by activity display unanticipated dynamics nearby the interface, where defects perform "U-turns" to keep away from the interface, push the interface to develop local fingers, or penetrate the interface to enter the opposite phase, driving interfacial morphogenesis and cross-interface defect transport. We identify that the emergent interfacial morphodynamics stems from the instability of the interface and is further driven by the activity-dependent defect-interface interactions. Experiments of interacting multicellular monolayers with extensile and contractile differences in cell activity have confirmed our predictions. These findings reveal a crucial role of topological defects in active-active interfaces during, for example, boundary formation and tissue competition that underlie organogenesis and clinically relevant disorders.

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