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1.
Nano Lett ; 24(23): 6872-6880, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38683656

RESUMEN

The efficient cytosolic delivery of the CRISPR-Cas9 machinery remains a challenge for genome editing. Herein, we performed ligand screening and identified a guanidinobenzol-rich polymer to overcome the cascade delivery barriers of CRISPR-Cas9 ribonucleoproteins (RNPs) for genome editing. RNPs were stably loaded into the polymeric nanoparticles (PGBA NPs) by their inherent affinity. The polymer facilitated rapid endosomal escape of RNPs via a dynamic multiple-step cascade process. Importantly, the incorporation of fluorescence in the polymer helps to identify the correlation between cellular uptake and editing efficiency, increasing the efficiency up to 70% from the initial 30% for the enrichment of edited cells. The PGBA NPs efficiently deliver RNPs for in vivo gene editing via both local and systemic injections and dramatically reduce PCSK9 level. These results indicate that PGBA NPs enable the cascade delivery of RNPs for genome editing, showing great promise in broadening the therapeutic potential of the CRISPR-Cas9 technique.


Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Nanopartículas , Polímeros , Edición Génica/métodos , Sistemas CRISPR-Cas/genética , Humanos , Polímeros/química , Nanopartículas/química , Animales , Ribonucleoproteínas/genética , Ribonucleoproteínas/química , Células HEK293 , Ratones , Guanidinas/química
2.
BMC Plant Biol ; 24(1): 296, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38632529

RESUMEN

BACKGROUND: Calcium-dependent protein kinases (CPKs) are crucial for recognizing and transmitting Ca2+ signals in plant cells, playing a vital role in growth, development, and stress response. This study aimed to identify and detect the potential roles of the CPK gene family in the amphidiploid Brassica carinata (BBCC, 2n = 34) using bioinformatics methods. RESULTS: Based on the published genomic information of B. carinata, a total of 123 CPK genes were identified, comprising 70 CPK genes on the B subgenome and 53 on the C subgenome. To further investigate the homologous evolutionary relationship between B. carinata and other plants, the phylogenetic tree was constructed using CPKs in B. carinata and Arabidopsis thaliana. The phylogenetic analysis classified 123 family members into four subfamilies, where gene members within the same subfamily exhibited similar conserved motifs. Each BcaCPK member possesses a core protein kinase domain and four EF-hand domains. Most of the BcaCPK genes contain 5 to 8 introns, and these 123 BcaCPK genes are unevenly distributed across 17 chromosomes. Among these BcaCPK genes, 120 replicated gene pairs were found, whereas only 8 genes were tandem duplication, suggesting that dispersed duplication mainly drove the family amplification. The results of the Ka/Ks analysis indicated that the CPK gene family of B. carinata was primarily underwent purification selection in evolutionary selection. The promoter region of most BcaCPK genes contained various stress-related cis-acting elements. qRT-PCR analysis of 12 selected CPK genes conducted under cadmium and salt stress at various points revealed distinct expression patterns among different family members in response to different stresses. Specifically, the expression levels of BcaCPK2.B01a, BcaCPK16.B02b, and BcaCPK26.B02 were down-regulated under both stresses, whereas the expression levels of other members were significantly up-regulated under at least one stress. CONCLUSION: This study systematically identified the BcaCPK gene family in B. carinata, which contributes to a better understanding the CPK genes in this species. The findings also serve as a reference for analyzing stress responses, particularly in relation to cadmium and salt stress in B. carinata.


Asunto(s)
Brassica , Brassica/genética , Filogenia , Cadmio/metabolismo , Familia de Multigenes , Genómica , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico/genética , Proteínas de Plantas/genética , Genoma de Planta
3.
Planta ; 259(5): 95, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38512412

RESUMEN

MAIN CONCLUSIONS: A novel image-based screening method for precisely identifying genotypic variations in rapeseed RSA under waterlogging stress was developed. Five key root traits were confirmed as good indicators of waterlogging and might be employed in breeding, particularly when using the MFVW approach. Waterlogging is a vital environmental factor that has detrimental effects on the growth and development of rapeseed (Brassica napus L.). Plant roots suffer from hypoxia under waterlogging, which ultimately confers yield penalty. Therefore, it is crucially important to understand the genetic variation of root system architecture (RSA) in response to waterlogging stress to guide the selection of new tolerant cultivars with favorable roots. This research was conducted to investigate RSA traits using image-based screening techniques to better understand how RSA changes over time during waterlogging at the seedling stage. First, we performed a t-test by comparing the relative root trait value between four tolerant and four sensitive accessions. The most important root characteristics associated with waterlogging tolerance at 12 h are total root length (TRL), total root surface area (TRSA), total root volume (TRV), total number of tips (TNT), and total number of forks (TNF). The root structures of 448 rapeseed accessions with or without waterlogging showed notable genetic diversity, and all traits were generally restrained under waterlogging conditions, except for the total root average diameter. Additionally, according to the evaluation and integration analysis of 448 accessions, we identified that five traits, TRL, TRSA, TRV, TNT, and TNF, were the most reliable traits for screening waterlogging-tolerant accessions. Using analysis of the membership function value (MFVW) and D-value of the five selected traits, 25 extremely waterlogging-tolerant materials were screened out. Waterlogging significantly reduced RSA, inhibiting root growth compared to the control. Additionally, waterlogging increased lipid peroxidation, accompanied by a decrease in the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). This study effectively improves our understanding of the response of RSA to waterlogging. The image-based screening method developed in this study provides a new scientific guidance for quickly examining the basic RSA changes and precisely predicting waterlogging-tolerant rapeseed germplasms, thus expanding the genetic diversity of waterlogging-tolerant rapeseed germplasm available for breeding.


Asunto(s)
Brassica napus , Brassica rapa , Fitomejoramiento , Plantones/fisiología , Fenotipo , Genotipo
4.
J Nanobiotechnology ; 22(1): 192, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38637848

RESUMEN

Androgen deprivation therapy (ADT) is a crucial and effective strategy for prostate cancer, while systemic administration may cause profound side effects on normal tissues. More importantly, the ADT can easily lead to resistance by involving the activation of NF-κB signaling pathway and high infiltration of M2 macrophages in tumor microenvironment (TME). Herein, we developed a biomimetic nanotherapeutic platform by deriving cell membrane nanovesicles from cancer cells and probiotics to yield the hybrid cellular nanovesicles (hNVs), loading flutamide (Flu) into the resulting hNVs, and finally modifying the hNVs@Flu with Epigallocatechin-3-gallate (EGCG). In this nanotherapeutic platform, the hNVs significantly improved the accumulation of hNVs@Flu-EGCG in tumor sites and reprogramed immunosuppressive M2 macrophages into antitumorigenic M1 macrophages, the Flu acted on androgen receptors and inhibited tumor proliferation, and the EGCG promoted apoptosis of prostate cancer cells by inhibiting the NF-κB pathway, thus synergistically stimulating the antitumor immunity and reducing the side effects and resistance of ADT. In a prostate cancer mouse model, the hNVs@Flu-EGCG significantly extended the lifespan of mice with tumors and led to an 81.78% reduction in tumor growth compared with the untreated group. Overall, the hNVs@Flu-EGCG are safe, modifiable, and effective, thus offering a promising platform for effective therapeutics of prostate cancer.


Asunto(s)
FN-kappa B , Neoplasias de la Próstata , Humanos , Masculino , Animales , Ratones , FN-kappa B/metabolismo , Andrógenos/uso terapéutico , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Inmunoterapia/métodos , , Línea Celular Tumoral , Microambiente Tumoral
5.
Int J Paediatr Dent ; 2024 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-38736091

RESUMEN

BACKGROUND: Referrals of paediatric patients to a university clinic have been increasing over the last several years. AIM: To evaluate characteristics of referred and non-referred patients at the University of Iowa's Pediatric Dental Clinic (UIPDC). DESIGN: A retrospective chart review included dental records of 340 referred and 383 non-referred patients from July 1, 2015, to May 31, 2016 (n = 723). Age, distance to the clinic, size of the patient's community, insurance, number of teeth with decay, treatment needs, educational level of the provider, and presence of patient special health care needs were obtained. Descriptive statistics, bivariate analysis, and multivariable logistic regression were performed to analyze the outcomes (alpha = .05). RESULTS: Referred patients were more likely to live >60 miles away, live in a community of >75 000 people, have special health care needs, have caries/greater number of teeth with decay, need endodontic treatment, and were less likely to remain patients at the clinic (p < .0001). Referred patients were also more likely to need extractions (p = .0104), but less likely to need space maintenance/comprehensive orthodontic treatment (p = .0002). CONCLUSION: There was a difference in the complexity of patient treatment needs between referred and non-referred patients.

6.
Zhongguo Zhong Yao Za Zhi ; 49(7): 1966-1973, 2024 Apr.
Artículo en Zh | MEDLINE | ID: mdl-38812209

RESUMEN

This study took Chinese patent medicine for children included in Chinese Pharmacopoeia(2020 edition and the first supplement), Medicine Catalogue for National Basic Medical Insurance, Work Injury Insurance, and Maternity Insurance(2022 edition), and National Essential Medicines List(2018 edition) as the research objects, so as to sort out the distribution situation, characteristics, and the problems of Chinese patent medicine for children(including child-specific medicines, common medicines for children and adults, and discretionary medicines for children). According to statistics and summary, Chinese patent medicine for children is mainly administered orally, and the dosage forms are mostly traditional dosage forms, such as tablets, granules, capsules, and oral liquids, with mostly bitter or sweet taste. Diseases are mainly classified into pulmonary diseases and spleen and stomach diseases, and varieties of medication without Children's medication safety information or "still unclear" account for a relatively large proportion of the medicines. There are relatively few varieties of Chinese patent medicines for children, poor compliance of child-specific medication, lack of refinement of Chinese patent medicines for children dosage, and lack of information about safe use of medication. It is recommended to update and improve the instruction manuals in a timely manner, develop new varieties of Chinese patent medicine for children, and actively carry out post-marketing evaluation and clinical comprehensive evaluation of Chinese patent medicine for children, so as to provide a reference for the supplement and improvement of the instructions, the comprehensive improvement, the formulation of the catalogue, and the research and development of new Chinese patent medicine for children and ensure the use of medicines for children.


Asunto(s)
Medicamentos Herbarios Chinos , Humanos , Niño , China , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos sin Prescripción , Medicina Tradicional China , Preescolar , Lactante , Adolescente
7.
J Med Virol ; 95(2): e28546, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36734063

RESUMEN

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening infectious disease caused by the SFTS virus (SFTSV). This study aimed to evaluate the predictive power of C-reactive protein to lymphocyte ratio (CLR) and establish an early-warning model for SFTS mortality. We retrospectively analyzed hospitalized SFTS patients in six clinical centers from May 2011 to 2022. The efficacy of CLR prediction was evaluated by the receiver operating characteristic (ROC) analysis. A nomogram was established and validated. Eight hundred and eighty-two SFTS patients (median age 64 years, 48.5% male) were enrolled in this study, with a mortality rate of 17.8%. The area under the ROC curve (AUC) of CLR was 0.878 (95% confidence interval [CI]: 0.850-0.903, p < 0.001), which demonstrates high predictive strength. The least absolute shrinkage and selection operator regression selected seven potential predictors. Multivariate logistic regression analysis determined three independent risk factors, including CLR, to construct the nomogram. The performance of the nomogram displayed excellent discrimination and calibration, with significant net benefits in clinical uses. CLR is a brand-new predictor for SFTS mortality. The nomogram based on CLR can serve as a convenient tool for physicians to identify critical SFTS cases in clinical practice.


Asunto(s)
Infecciones por Bunyaviridae , Phlebovirus , Síndrome de Trombocitopenia Febril Grave , Humanos , Masculino , Persona de Mediana Edad , Femenino , Proteína C-Reactiva/análisis , Estudios Retrospectivos , Factores de Riesgo , China
9.
Environ Res ; 231(Pt 2): 116222, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37224951

RESUMEN

Endocrine-disrupting chemicals (EDCs) widely exist in people's production and life which have great potential to damage human and animal health. Over the past few decades, growing attention has been paid to the impact of EDCs on human health, as well as immune system. So far, researchers have proved that EDCs (such as bisphenol A (BPA), phthalate, tetrachlorodibenzodioxin (TCDD), etc.) affect human immune function and promotes the occurrence and development of autoimmune diseases (ADs). Therefore, in order to better understand how EDCs affect ADs, we summarized the current knowledge about the impact of EDCs on ADs, and elaborated the potential mechanism of the impact of EDCs on ADs in this review.


Asunto(s)
Enfermedades Autoinmunes , Disruptores Endocrinos , Dibenzodioxinas Policloradas , Animales , Humanos , Disruptores Endocrinos/toxicidad , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/epidemiología , Sistema Inmunológico
10.
Proc Natl Acad Sci U S A ; 117(44): 27141-27147, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33024017

RESUMEN

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.


Asunto(s)
Infecciones por Coronavirus/terapia , Citocinas/antagonistas & inhibidores , Nanopartículas/uso terapéutico , Neumonía Viral/terapia , Internalización del Virus/efectos de los fármacos , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus , COVID-19 , Membrana Celular/química , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Células HEK293 , Humanos , Interleucina-6/antagonistas & inhibidores , Ratones , Ratones Endogámicos ICR , Monocitos , Nanopartículas/química , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Receptores de Citocinas/metabolismo , SARS-CoV-2 , Células THP-1
11.
Prep Biochem Biotechnol ; 53(9): 1058-1066, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36719814

RESUMEN

The biomass of Lactobacillus strains depends on the culture media and culture conditions. The purpose of this study was to optimize the culture medium composition and culture conditions of Lactobacillus plantarum Y44 to improve its biomass. The utilization of different carbon sources and nitrogen sources by L. plantarum Y44 was assessed by single factor experiment to screen out the economical carbon and nitrogen sources for L. plantarum Y44 growth. Through optimization experiments, the optimized culture medium for L. plantarum Y44 growth consists of soybean peptone 44.1 g/L, yeast extract 22.1 g/L, sucrose 35.6 g/L, hydrogen diamine citrate 2 g/L, anhydrous sodium acetate 8.5 g/L, dipotassium hydrogen phosphate 4 g/L, Tween-80 2 mL/L, manganese sulfate 0.25 g/L, and magnesium sulfate 0.58 g/L, and the initial pH 6.7. The concentration of viable bacteria cells of L. plantarum Y44 culturing in the optimized medium at 37 °C for 16 h was up to 3.363 × 1010 CFU/mL, as 6.11 times higher than that in the MRS medium.


Asunto(s)
Lactobacillus plantarum , Medios de Cultivo/química , Lactobacillus , Carbono , Nitrógeno
12.
J Prosthodont ; 2023 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-37964664

RESUMEN

PURPOSE: Older adults with removable dentures experience high rates of both caries (when the natural dentition remains) and salivary gland dysfunction. While many commercial dental therapeutic agents target these two interrelated problems, none have been labeled for use on the fitting surface of removable dentures. Off-label use of MI Paste (GC America, Alsip, IL), a dental therapeutic containing casein-phosphopeptide-amorphous-calcium-phosphate (CPP-ACP), was investigated following its application to the fitting surface of complete denture(s) with subsequent effects on salivary conditions measured. MATERIALS AND METHODS: Salivary flow rate and pH were recorded at baseline and 15 min following the application of 1 mL of CPP-ACP paste to the fitting surface of each participant's denture through whole saliva collection. To assess buffering capacity, equivalent volumes of 0.01 M lactic acid were added to the collected saliva samples, and pH reduction was measured. Comparisons of salivary parameters between baseline and post-CPP-ACP paste application and between subjects with and without self-reported xerostomia were conducted using a paired-sample t-test, Wilcoxon signed-rank test, or two-sample t-test as appropriate. RESULTS: Of the 28 participants (mean age = 70.3 ± 13.7 years, 17 males), 11 reported xerostomia. CPP-ACP-paste application was associated with decreased pH reduction during acid challenge compared to baseline (0.95 ± 0.24 vs. 1.54 ± 0.53, p < 0.001), and a higher final pH following acid challenge (5.93 ± 0.34 vs. 5.40 ± 0.66, p < 0.001). While the flow rates observed at post-CPP-ACP paste application were greater than those at baseline, the difference was not statistically significant (0.67 ± 0.44 mL/min vs. 0.55 ± 0.34 mL/min, p = 0.053). No significant differences were found in any salivary parameters between participants with or without self-reports of xerostomia. CONCLUSIONS: The findings highlight potential positive effects on salivary conditions following the application of the CPP-ACP-containing product, MI Paste, to the fitting surface of a removable complete denture as a potential caries-risk-management tool when natural dentition remains. Determining the caries-preventive clinical significance will require longer-term trials.

13.
Anal Chem ; 94(29): 10479-10486, 2022 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-35834188

RESUMEN

As the key player of a new restriction modification system, DNA phosphorothioate (PT) modification, which swaps oxygen for sulfur on the DNA backbone, protects the bacterial host from foreign DNA invasion. The identification of PT sites helps us understand its physiological defense mechanisms, but accurately quantifying this dynamic modification remains a challenge. Herein, we report a simple quantitative analysis method for optical mapping of PT sites in the single bacterial genome. DNA molecules are fully stretched and immobilized in a microfluidic chip by capillary flow and electrostatic interactions, improving the labeling efficiency by maximizing exposure of PT sites on DNA while avoiding DNA loss and damage. After screening 116 candidates, we identified a bifunctional chemical compound, iodoacetyl-polyethylene glycol-biotin, that can noninvasively and selectively biotinylate PT sites, enabling further labeling with streptavidin fluorescent nanoprobes. With this method, PT sites in PT+ DNA can be easily detected by fluorescence, while almost no detectable ones were found in PT- DNA, achieving real-time visualization of PT sites on a single DNA molecule. Collectively, this facile genome-wide PT site detection method directly characterizes the distribution and frequency of DNA modification, facilitating a better understanding of its modification mechanism that can be potentially extended to label DNAs in different species.


Asunto(s)
Genoma Bacteriano , Microfluídica , ADN , ADN Bacteriano/genética , Azufre
14.
Small ; 18(12): e2106253, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35083839

RESUMEN

2D materials with intriguing properties have been widely used in optoelectronics. However, electronic devices suffered from structural damage due to the ultrathin materials and uncontrolled defects at interfaces upon metallization, which hindered the development of reliable devices. Here, a damage-free Au/h-BN/Au memristor is reported using a clean, water-assisted metal transfer approach by physically assembling Au electrodes onto the layered h-BN which minimized the structural damage and undesired interfacial defects. The memristors demonstrate significantly improved performance with the coexistence of nonpolar and threshold switching as well as tunable current levels by controlling the compliance current, compared with devices with evaporated contacts. The devices integrated into an array show suppressed sneak path current and can work as both logic gates and latches to implement logic operations allowing in-memory computing. Cross-sectional scanning transmission electron microscopy analysis validates the feasibility of this nondestructive metal integration approach, the crucial role of high-quality atomically sharp interface in resistive switching, and a direct observation of percolation path. The underlying mechanism of boron vacancies-assisted transport is further supported experimentally by conductive atomic force microscopy free from process-induced damage, and theoretically by ab initio simulations.

15.
Electrophoresis ; 43(21-22): 2062-2073, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35621205

RESUMEN

The effects of fluid slippage on the pressure-driven electrokinetic energy conversion in conical nanochannels are systematically investigated in this paper. We present a multiphysical model that couples the Planck-Nernst-Poisson equations and the Navier-Stokes equation with a Navier slip condition to fulfill this purpose. We systematically look into the variation of various performance indicators of electrokinetic energy conversion, for example, streaming current, streaming potential, generation power, energy conversion efficiency, regulation parameter, and enchantment ratio, with the conicity of nanochannels and the slip length for two pressure differences of the same magnitude but opposite directions. Particularly, enhancement ratios related to streaming current, streaming potential, generation power, and energy conversion efficiency are defined to comprehensively measure the enhancement of the performance of electrokinetic energy conversion due to the slip length. The results demonstrate that a combination of large slip length and small conicity enhances the electrokinetic energy conversion performance significantly. Furthermore, the fluid slippage-induced enhancement of the electrokinetic energy conversion in the backward pressure difference mode is stronger than that in the forward pressure difference mode. Our results provide design and operation guidelines for pressure-driven electrokinetic energy conversion devices.

16.
Mol Pharm ; 19(12): 4675-4684, 2022 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-36349888

RESUMEN

Dentin biomodification is a promising approach to enhance dental tissue biomechanics and biostability for restorative and reparative therapies. One of the most active dentin tissue biomodifiers is proanthocyanidin (PAC)-rich natural extracts, which are used in the dental bonding procedure in combination with resin-based adhesives (RBAs). This study aimed to investigate the use of mesoporous silica nanoparticles (MSNs) for the sustained delivery of PACs for dentin biomodification as a novel drug-delivery system for dental applications. The effects of the incorporation of MSN functionalized with 3-aminopropyltriethoxysilane (APTES) and loaded with PAC into an experimental RBA were assessed by characterizing the material mechanical properties. In addition, the immediate and long-term bonding performance of an experimental resin-based primer (RBP) containing MSN-APTES loaded with PAC was also evaluated. For that, different formulations of RBA and RBP were prepared containing 20% w/v MSN-APTES loaded with PAC before or after functionalization (MSN-PAC-APTES and MSN-APTES-PAC, respectively). The incorporation of MSN-APTES-PAC did not negatively impact the degree of conversion or the overall mechanical properties of the RBA. However, adding MSN-PAC-APTES resulted in inferior mechanical properties of the experimental RBA. In the adhesion studies, APTES-functionalized MSN was successfully added to an experimental RBP for drug-delivery purposes without compromising the bond strength to the dentin or the failure mode. Interestingly, the sequence of surface functionalization with APTES resulted in differences in the bonding performance, with better long-term results for RBP containing MSN loaded with PAC after functionalization.


Asunto(s)
Nanopartículas , Proantocianidinas , Dióxido de Silicio/química , Proantocianidinas/química , Nanopartículas/química , Silanos/química
17.
Nature ; 537(7618): 50-6, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27582220

RESUMEN

Alzheimer's disease (AD) is characterized by deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aß to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aß. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aß, and reduce soluble and insoluble Aß in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aß in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/efectos de los fármacos , Amiloide/metabolismo , Péptidos beta-Amiloides/química , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ensayos Clínicos Fase III como Asunto , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Modelos Biológicos , Placa Amiloide/patología , Agregación Patológica de Proteínas/tratamiento farmacológico , Solubilidad
18.
Acta Pharmacol Sin ; 43(1): 157-166, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33758355

RESUMEN

Long noncoding RNAs (lncRNAs) are involved in a variety of cancers, but the role of LncRNA DUBR in lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, remains unclear. In this study we investigated the expression of DUBR in LUAD to ascertain its association with the clinical pathology and prognosis of LUAD. Analysis of mRNA expression in The Cancer Genome Atlas (TCGA) LUAD database and in-house LUAD cohort (n = 94) showed that DUBR was significantly downregulated in LUAD, and was associated with poor prognosis. In LUAD cell lines (H1975, A549), overexpression of DUBR significantly suppressed the migration and invasion of the LUAD cells. We demonstrated that c-Myc could bind to the promoter of DUBR, and transcriptionally suppressed its expression. Knockdown of c-Myc almost completely blocked the invasion and migration of LUAD cells, whereas knockdown of DUBR partially rescued c-Myc-knockdown suppressed cell migration and invasion. Furthermore, DUBR overexpression significantly increased the expression of a downstream protein of DUBR, zinc finger, and BTB domain containing 11 (ZBTB11), in H1975 and A549 cells; knockdown of ZBTB11 partially rescued the DUBR-overexpression suppressed cell migration and invasion; knockdown of c-Myc significantly upregulated the expression of ZBTB11 in LUAD cells. Finally, we revealed that DUBR/ZBTB11 axis suppressed oxidative phosphorylation in LUAD cells. In short, we demonstrate that c-Myc/DUBR/ZBTB11 axis suppresses migration and invasion of LUAD by attenuating cell oxidative phosphorylation, which provides new insights into the regulatory mechanism of DUBR.


Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , ARN Largo no Codificante/metabolismo , Adenocarcinoma del Pulmón/diagnóstico , Dominio BTB-POZ , Movimiento Celular , Proteínas de Unión al ADN/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/diagnóstico , Estructura Molecular , Fosforilación Oxidativa , ARN Largo no Codificante/genética , Relación Estructura-Actividad , Factores de Transcripción/metabolismo
19.
Int J Mol Sci ; 23(21)2022 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-36361657

RESUMEN

Clubroot caused by Plasmodiophora brassicae led to a significant decrease in the yield and quality of Brassica napus, one of the most important oil crops in the world. JAZ proteins are an essential repressor of jasmonates (JAs) signaling cascades, which have been reported to regulate the resistance to P. brassicae in B. napus. In this study, we identified 51, 25 and 26 JAZ proteins in B. napus, B. rapa and B. oleracea, respectively. Phylogenetic analysis displayed that the notedJAZ proteins were divided into six groups. The JAZ proteins clustered in the same group shared a similar motif composition and distribution order. The 51 BnaJAZs were not evenly assigned on seventeen chromosomes in B. napus, except for A04 and C07. The BnaJAZs of the AtJAZ7/AtJAZ8 group presented themselves to be significantly up-regulated after inoculation by P. brassicae. Variation analysis in a population with a specific resistance performance in P. brassicae displayed a 64 bp translocation in BnaC03T0663300ZS (BnaJAZ8.C03, homologous to AtJAZ8) with an 8% reduction in the disease index on average. Through protein-protein interaction analysis, 65 genes were identified that might be involved in JAZ8 regulation of resistance to P. brassicae in B. napus, which provided new clues for understanding the resistance mechanism to P. brassicae.


Asunto(s)
Brassica napus , Plasmodiophorida , Plasmodiophorida/fisiología , Brassica napus/genética , Resistencia a la Enfermedad/genética , Filogenia , Enfermedades de las Plantas/genética
20.
Electrophoresis ; 42(3): 257-268, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33111983

RESUMEN

This paper utilizes a combined approach of the convection-diffusion theory and the moment analysis to conduct a comprehensive investigation of the solute dispersion under the influence of the interphase transport in finitely long inner coated microchannels. The present work has threefold novel contributions: (1) The 2D solute concentration contours in the stationary phase are calculated for the first time to facilitate the understanding the role of the interphase transport in the solute dispersion in the mobile phase. (2) The skewness of the elution curves is investigated to guide the control of solute band shape at the channel outlet. (3) The 2D diffusion-convection theory and zero-dimensional (0D) moment analysis complement each other to present a characterization of the solute dispersion behaviors more comprehensive than that by either of the two methods alone. Parametric studies are performed to clarify the effects of four major parameters related to the interphase transport (i.e., stationary phase Péclet number, interphase transport rate, partition coefficient, and stationary phase thickness) on the solute dispersion characteristics. The results from this study provide a straightforward understanding of the effects of interphase transport on the solute dispersion in finitely long microchannels and are of potential relevance to the design and operation of the microfluidics-based analytical devices.


Asunto(s)
Simulación por Computador , Dispositivos Laboratorio en un Chip , Técnicas Analíticas Microfluídicas/métodos , Soluciones/química , Diseño de Equipo , Reproducibilidad de los Resultados
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