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1.
Small ; 17(46): e2103091, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34643034

RESUMO

Hydrogel electrolytes have attracted enormous attention in flexible and safe supercapacitors. However, the interfacial contact problem between hydrogel electrolyte and electrodes, and the environmental instability are the key factors restricting the development of hydrogel-based supercapacitors. Here, a nucleotide-tackified adhesive organohydrogel electrolyte is successfully constructed and exhibits freezing resistance and water-holding ability based on the water/glycerol binary solvent system. Adenosine monophosphate enables the organohydrogels to possess outstanding adhesion and mechanical robustness. The robust adhesion can ensure close contact between the organohydrogel electrolyte and electrodes for constructing an all-in-one supercapacitor with low interfacial contact resistance. Impressively, the integrated organohydrogel-based supercapacitors display an areal specific capacitance of 163.6 mF cm-2 . Besides, the supercapacitors feature prominent environmental stability with capacitance retention of 90.6% after 5000 charging/discharging cycles at -20 °C. Furthermore, based on the strong interfacial adhesion, the supercapacitors present excellent electrochemical stability without delamination/displacement between electrolyte and electrodes even under severe deformations such as bending and twisting. It is anticipated that this work will provide an encouraging way for developing flexible energy storage devices with electrochemical stability and environmental adaptability.

2.
Neural Netw ; 144: 372-383, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34555664

RESUMO

This paper concerns the multisynchronization issue for delayed fractional-order memristor-based neural networks with nonlinear coupling and almost-periodic perturbations. First, the coexistence of multiple equilibrium states for isolated subnetwork is analyzed. By means of state-space decomposition, fractional-order Halanay inequality and Caputo derivative properties, the novel algebraic sufficient conditions are derived to ensure that the addressed networks with arbitrary activation functions have multiple locally stable almost periodic orbits or equilibrium points. Then, based on the obtained multistability results, a pinning control strategy is designed to realize the multisynchronization of the N coupled networks. By the aid of graph theory, depth first search method and pinning control law, some sufficient conditions are formulated such that the considered neural networks can possess multiple synchronization manifolds. Finally, the multistability and multisynchronization performance of the considered neural networks with different activation functions are illustrated by numerical examples.


Assuntos
Algoritmos , Redes Neurais de Computação
3.
Angew Chem Int Ed Engl ; 60(50): 26087-26095, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34490693

RESUMO

Synthetic molecular robots can execute sophisticated molecular tasks at nanometer resolution. However, a molecular robot capable of controlling cellular behavior remains unexplored. Herein, we report a self-propelled DNA robot operating on the cell membrane to control the migration of a cell. Driven by DNAzyme catalytic activity, the DNA robot could autonomously and stepwise move on the membrane-floating cell-surface receptors in a stochastic manner and simultaneously trigger the receptor-dimerization to activate downstream signaling for cell motility. The cell membrane-associated continuous motion and operation of a DNA robot allowed for the ultrasensitive regulation of MET/AKT signaling and cytoskeleton remodeling to enhance cell migration. Finally, we designed distinct conditional DNA robots to orthogonally manipulate the cell migration in a coculture of mixed cell populations. We have developed a novel strategy to engineer a cell-driving molecular robot, representing a promising avenue for precise cell manipulation with nanoscale resolution.

4.
Clin Exp Pharmacol Physiol ; 48(12): 1613-1620, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34343357

RESUMO

Cerebral vasospasm (CVS) is a frequent and serious neurosurgical complication, without sufficient therapy. This retrospective study was performed to analyze if nimodipine can improve prognosis and reduce ischaemia secondary to delayed CVS after intracranial tumour surgery. A retrospective review was performed over the years 2011 to 2012 for patients with an anterior cranial fossa tumour and underwent intracranial tumour surgery. The surgical field was soaked with nimodipine solution or normal saline. Transcranial Doppler ultrasonography was used to measure velocity in the middle cerebral artery (MCA) and the distal extracranial internal carotid artery (eICA). Follow-up was performed using the Glasgow Outcome Scale (GOS) after discharge. There were 94 patients that met the inclusion criteria. They included 50 males and 44 females, with a mean age of 49.6 years. In the nimodipine group, CVS occurred in 13 patients; 9 patients had CVS between 4 and 7 days, and 4 had CVS between 8 and 14 days. In the normal saline group, 19 patients had CVS, 3 presented with CVS within 3 days, 11 between 4-7 days and 5 between 8-14 days. A significant difference in the occurrence of CVS was observed between the two groups. Preoperative and postoperative the MCA velocities were compared, revealing a significant change in the normal saline group but not in the nimodipine group. Nimodipine markedly improves prognosis and significantly reduces ischaemia secondary to delayed CVS after intracranial tumour surgery, as well as the risks of mortality and morbidity.

5.
Genome Med ; 13(1): 125, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365978

RESUMO

BACKGROUND: Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination. METHODS: This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment. RESULTS: Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of - 0.50, 95% CI [- 0.85, - 0.15] mmol/L, and - 0.55, 95% CI [- 0.91, - 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline. CONCLUSIONS: Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017.

6.
Nat Commun ; 12(1): 4113, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226540

RESUMO

Tri-methylation on lysine 40 of α-tubulin (α-TubK40me3) is a recently identified post-translational modification involved in mitosis and cytokinesis. However, knowledge about α-TubK40me3 in microtubule function and post-mitotic cells remains largely incomplete. Here, we report that α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation. α-TubK40me3 is enriched in mouse cerebral cortex during embryonic day (E)14 to E16. Knockdown of α-tubulin methyltransferase SETD2 at E14 leads to the defects in neuronal migration, which could be restored by overexpressing either a cytoplasm-localized SETD2 truncation or α-TubK40me3-mimicking mutant. Furthermore, α-TubK40me3 is preferably distributed on polymerized microtubules and potently promotes tubulin nucleation. Downregulation of α-TubK40me3 results in reduced microtubule abundance in neurites and disrupts neuronal polarization, which could be rescued by Taxol. Additionally, α-TubK40me3 is increased after losing α-tubulin K40 acetylation (α-TubK40ac) and largely rescues α-TubK40ac function. This study reveals a critical role of α-TubK40me3 in microtubule formation and neuronal development.


Assuntos
Movimento Celular , Microtúbulos/metabolismo , Neurônios/metabolismo , Tubulina (Proteína)/metabolismo , Acetilação , Animais , Córtex Cerebral , Citocinese , Técnicas de Silenciamento de Genes , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Lisina/metabolismo , Metilação , Camundongos , Mitose , Neurogênese , Paclitaxel , Processamento de Proteína Pós-Traducional
7.
Front Oncol ; 11: 627556, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854966

RESUMO

Gastric cancer is the second most lethal type of malignant tumor in the world. Early diagnosis of gastric cancer can reduce the transformation to advanced cancer and improve the early treatment rate. As a cheap, real-time, non-invasive examination method, oral contrast-enhanced ultrasonography (OCUS) is a more acceptable way to diagnose gastric cancer than interventional diagnostic methods such as gastroscopy. In this paper, we proposed a new method for the diagnosis of gastric diseases by automatically analyzing the hierarchical structure of gastric wall in gastric ultrasound images, which is helpful to quantify the diagnosis information of gastric diseases and is a useful attempt for early screening of gastric cancer. We designed a gastric wall detection network based on U-net. On this basis, anisotropic diffusion technology was used to extract the layered structure of the gastric wall. A simple and useful gastric cancer screening model was obtained by calculating and counting the thickness of the five-layer structure of the gastric wall. The experimental results showed that our model can accurately identify the gastric wall, and it was found that the layered parameters of abnormal gastric wall is significantly different from that of normal gastric wall. For the screening of gastric disease, a statistical model based on gastric wall stratification can give a screening accuracy of 95% with AUC of 0.92.

8.
J Mol Cell Biol ; 13(2): 91-103, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33394042

RESUMO

Microtubules (MTs) are regulated by a number of known posttranslational modifications (PTMs) on α/ß-tubulin to fulfill diverse cellular functions. Here, we showed that SUMOylation is a novel PTM on α-tubulin in vivo and in vitro. The SUMOylation on α-tubulin mainly occurred at Lys 96 (K96), K166, and K304 of soluble α-tubulin and could be removed by small ubiquitin-related modifier (SUMO)-specific peptidase 1. In vitro experiments showed that tubulin SUMOylation could reduce interprotofilament interaction, promote MT catastrophe, and impede MT polymerization. In cells, mutation of the SUMOylation sites on α-tubulin reduced catastrophe frequency and increased the proportion of polymerized α-tubulin, while upregulation of SUMOylation with fusion of SUMO1 reduced α-tubulin assembly into MTs. Additionally, overexpression of SUMOylation-deficient α-tubulin attenuated the neurite extension in Neuro-2a cells. Thus, SUMOylation on α-tubulin represents a new player in the regulation of MT properties.

9.
Ann Surg ; 273(3): 523-531, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31058700

RESUMO

OBJECTIVE: This study was intended to identify prognostic biomarkers for lymph node (LN)-positive locoregional esophageal squamous cell carcinoma (ESCC) patients. SUMMARY OF BACKGROUND DATA: Surgery is a major treatment for LN-positive locoregional ESCC patients in China. However, patient outcomes are poor and heterogeneous. METHODS: ESCC-associated miRNAs were identified by microarray and validated by quantitative real-time polymerase chain reaction analyses in ESCC and normal esophageal epithelial samples. A multi-miRNA based classifier was established using a least absolute shrinkage and selection operator model in a training set of 145 LN-positive locoregional ESCCs, and further assessed in internal testing and independent validation sets of 145 and 243 patients, respectively. RESULTS: Twenty ESCC-associated miRNAs were identified and validated. A 4-miRNA based classifier (miR-135b-5p, miR-139-5p, miR-29c-5p, and miR-338-3p) was generated to classify LN-positive locoregional ESCC patients into high and low-risk groups. Patients with high-risk scores in the training set had a lower 5-year overall survival rate [8.7%, 95% confidence interval (CI): 0-20.3] than those with low-risk scores (50.3%, 95% CI: 40.0-60.7; P < 0.0001). The prognostic accuracy of the classifier was validated in the internal testing (P < 0.0001) and independent validation sets (P = 0.00073). Multivariate survival analyses showed that the 4-miRNA based classifier was an independent prognostic factor, and the combination of the 4-miRNA based classifier and clinicopathological prognostic factors significantly improved the prognostic accuracy of clinicopathological prognostic factors alone. CONCLUSION: Our 4-miRNA based classifier is a reliable prognostic prediction tool for overall survival in LN-positive locoregional ESCC patients and might offer a novel probability of ESCC treatment individualization.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/cirurgia , MicroRNAs/genética , Idoso , Biomarcadores Tumorais/genética , China , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
10.
Anal Chem ; 92(24): 16314-16321, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33259185

RESUMO

Proteases play crucial roles in the malignant progression of tumor and thus have been regarded as biomarkers for many cancers. Although protease assays such as immunoassays and fluorogenic substrate probes have been developed, it remains challenging for them to give consideration to both sensitivity and accuracy. Here, we describe a proteolysis-responsive rolling circle transcription assay (PRCTA) for the ultrasensitive and accurate detection of protease activities by the rational integration of a protease-responsive RNA polymerase and rolling circle transcription. Taking cancer biomarker matrix metalloproteinase-2 (MMP-2) as the model, the PRCTA, which can transduce and amplify each proteolysis event catalyzed by MMP-2 into the output of multiple tandem fluorescent RNAs by in vitro transcription, is constructed for the sensitive analysis of MMP-2 activities. Such a rational integration greatly enhances the signal gain in PRCTA, and it enables the limit of detection of MMP-2 as low as 3 fM. The feasibility of PRCTA has been validated by the sensitive analysis of cellular MMP-2 activities of different cell lines with good accuracy, and the readout can be readily visualized by a fluorescence imaging system. Therefore, PRCTA has achieved the detection of target protease biomarkers with femtomolar sensitivity, exhibiting promising potential in biomedicine research and cancer diagnosis.


Assuntos
Limite de Detecção , Metaloproteinase 2 da Matriz/metabolismo , Técnicas de Amplificação de Ácido Nucleico/métodos , Proteólise , Biomarcadores/metabolismo , Humanos
11.
Sensors (Basel) ; 21(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379408

RESUMO

Bandwidth is the crucial knowledge to sampling, reconstruction or estimation of the graph signal (GS). However, it is typically unknown in practice. In this paper, we focus on detecting the bandwidth of bandlimited GS with a small sample size, where the number of spectral components of GS to be tested may greatly exceed the sample size. To control the significance of the result, the detection procedure is implemented by multi-stage testing. In each stage, a Bayesian score test, which introduces a prior to the spectral components, is adopted to face the high dimensional challenge. By setting different priors in each stage, we make the test more powerful against alternatives that have similar bandwidth to the null hypothesis. We prove that the Bayesian score test is locally most powerful in expectation against the alternatives following the given prior. Finally, numerical analysis shows that our method has a good performance in bandwidth detection and is robust to the noise.

12.
Anal Chem ; 92(22): 15194-15201, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33136382

RESUMO

Neurotransmitters are essential chemical mediators for neuronal communication in variable neuromodulations. However, the progress of neuroscience is hampered by the shortage of suitable sensors to track neurotransmitters with high spatial and temporal resolution. Here, we introduce a self-assembled DNA-nanoprism fluorescent probe capable of nongenetically engineering the cell surface for ultrasensitive imaging of the neurotransmitter release at a single live-cell level. The DNA-nanoprism structure conjugated with three cholesterol tails enables the probe to rapidly and stably anchor on the cell surface within 10 min. The in situ detection of neurotransmitters is achieved by equipping the DNA-nanoprism with an aptamer-based "turn-on" fluorescent sensory module for the transmitter of interest. In a proof-of-concept study, we directly visualized the transient dopamine (DA) release on the cell surface with selective responsivity and high spatiotemporal precision and further explored the dynamic correlation between DA release and calcium influx triggered by high K+. This study provides a robust and sensitive tool for cell-surface-targeted imaging of neuromodulations, which might open up a new avenue to improve the understanding of neurochemistry and advance neuroscience research.


Assuntos
DNA/química , Corantes Fluorescentes/química , Nanoestruturas/química , Neurotransmissores/química , Neurotransmissores/metabolismo , Imagem Óptica/métodos , Linhagem Celular Tumoral , Sobrevivência Celular , Dopamina/metabolismo , Humanos , Neurônios/citologia
13.
Exp Ther Med ; 20(3): 2252-2261, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32765702

RESUMO

MicroRNAs (miRNAs) are increasingly recognized as important regulators of non-small cell lung cancer (NSCLC) progression by directly regulating their target genes. The aim of the present study was to assess the biological role of miR-19a-3p in NSCLC. It was revealed that miR-19a-3p expression was significantly downregulated in human NSCLC tissues and cell lines compared with normal tissues and lung epithelial cells. In addition, a lower miR-19a-3p expression was significantly associated with Tumor Node Metastasis stage and lymph node metastasis. Furthermore, the upregulation of miR-19a-3p in NSCLC cell lines significantly inhibited cell proliferation, migration and invasion, as determined using an MTT, colony formation, wound healing and transwell Matrigel invasion assays, respectively. A luciferase reporter assay and western blotting determined that ubiquitin associated protein 2 like (UBAP2L) was a direct target of miR-19a-3p and could be inhibited through the upregulation of miR-19a-3p in NSCLC. In addition, UBAP2L silencing induced similar effects to those observed following miR-19a-3p overexpression. The overexpression of UBAP2L partially reversed the effects of miR-19a-3p on NSCLC cell lines. Collectively, these data indicated that miR-19a-3p may serve as a tumor suppressor partly through the regulation of UBAP2L expression in NSCLC and that the targeting of miR-19a-3p may be a novel method for NSCLC treatment.

15.
Biomolecules ; 10(4)2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331205

RESUMO

Spermatogenesis is a continuous and dynamic developmental process, in which a single diploid spermatogonial stem cell (SSC) proliferates and differentiates to form a mature spermatozoon. Herein, we summarize the accumulated knowledge of SSCs and their distribution in the testes of teleosts. We also reviewed the primary endocrine and paracrine influence on spermatogonium self-renewal vs. differentiation in fish. To provide insight into techniques and research related to SSCs, we review available protocols and advances in enriching undifferentiated spermatogonia based on their unique physiochemical and biochemical properties, such as size, density, and differential expression of specific surface markers. We summarize in vitro germ cell culture conditions developed to maintain proliferation and survival of spermatogonia in selected fish species. In traditional culture systems, sera and feeder cells were considered to be essential for SSC self-renewal, in contrast to recently developed systems with well-defined media and growth factors to induce either SSC self-renewal or differentiation in long-term cultures. The establishment of a germ cell culture contributes to efficient SSC propagation in rare, endangered, or commercially cultured fish species for use in biotechnological manipulation, such as cryopreservation and transplantation. Finally, we discuss organ culture and three-dimensional models for in vitro investigation of fish spermatogenesis.


Assuntos
Técnicas de Cultura de Células , Separação Celular , Peixes/metabolismo , Espermatogônias/citologia , Células-Tronco/citologia , Animais , Masculino , Espermatogênese , Espermatogônias/ultraestrutura , Células-Tronco/ultraestrutura
16.
Artigo em Inglês | MEDLINE | ID: mdl-31793415

RESUMO

AIMS AND OBJECTIVE: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common chronic kidney disease that leads to End-Stage Renal Disease (ESRD). The key target of this therapy is to prevent the progression of kidney failure. Tolvaptan could slow kidney cyst growth and are proven highly effective. The aims of this analysis are to perform a systematic review, estimate and evaluate the efficacy and safety of tolvaptan in ADPKD patients. MATERIALS AND METHODS: Randomized controlled trials of tolvaptan in ADPKD were identified in PubMed, Ovid, Web of Science and the Cochrane Library electronic database. The changes observed in kidney function, treatment efficiency and the incidence of adverse events between the tolvaptan and placebo groups were compared. Data were analyzed by the RevMan software. RESULTS: Eight trials, including 7 double-blinded randomised controlled trials and 1 quasi RCT involving 1,536 patients were extracted. Significant differences in the annual rate of change in the total kidney volume TKV at any stages of CKD (MD = -3.32, 95%CI =-4.57,-2.07, I2 =70%) and the glomerular filtration rate (MD = 1.4, 95%CI = 0.83,1.97, I2 =0%) were observed between the tolvaptan group and the placebo group. Subgroup analysis of patients in different CKD stages also showed the same conclusion. There was an increase in the urine osmolality, and 24-hour urine volume in patients receiving tolvaptan. Tolvaptan reduced the rate of serious hypertension and kidney pain events in ADPKD patients. At higher doses, it increased the rate of adverse events (liver injuries, thirst, pollakiuria, and nocturia). There was no significant risk of bias in the included studies. CONCLUSION: Tolvaptan has a beneficial effect on ADPKD, but is associated with an increase in adverse events at high doses when compared with the placebo. Further RCTs on tolvaptan may be required to support this conclusion.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Tolvaptan/efeitos adversos , Tolvaptan/uso terapêutico , Humanos , Rim Policístico Autossômico Dominante/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Toxicol Lett ; 315: 77-86, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470059

RESUMO

T-2 toxin is a major pollutant in crops and feedstuffs. Due to its high toxicity in a variety of organisms, T-2 toxin is of great concern as a threat to humans and to animal breeding. Overexpression of CYP1A1 may contribute to carcinogenesis, and CYP1A1 may be a promising target for the prevention and treatment of human malignancies. Therefore, it is essential to understand the regulatory mechanism by which T-2 toxin induces CYP1A1 expression in human cells. In this study, we confirmed that T-2 toxin (100 ng/mL) induced the expression of CYP1A1 in HepG2 cells through NRF1 and Sp1 bound to the promoter instead of through the well-recognized Aromatic hydrocarbon receptors (AhR). In cells treated with T-2 toxin, Sp1, but not NRF1, was significantly upregulated. However, T-2 toxin apparently promoted the interaction between NRF1 and Sp1 proteins, as revealed by IP analysis. Furthermore, in T-2 toxin-treated HepG2 cells, nuclear translocation of NRF1 was enhanced, while knockdown of Sp1 ablated NRF1 nuclear enrichment. Our results revealed that the upregulation of CYP1A1 by T-2 toxin in HepG2 cells depended on enhanced interaction between Sp1 and NRF1. This finding suggests the tumorigenic features of T-2 toxin might be related to the CYP1A1, which provides new insights to understand the toxicological effect of T-2 toxin.


Assuntos
Citocromo P-450 CYP1A1/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 1 Relacionado a NF-E2/genética , Fator de Transcrição Sp1/genética , Toxina T-2/toxicidade , Regulação para Cima/efeitos dos fármacos , Carcinoma/fisiopatologia , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Pesquisas com Embriões , Regulação Enzimológica da Expressão Gênica , Humanos , Rim , Neoplasias Hepáticas/fisiopatologia , Fator 1 Relacionado a NF-E2/efeitos dos fármacos , Fator 1 Relacionado a NF-E2/metabolismo , Fator de Transcrição Sp1/efeitos dos fármacos , Fator de Transcrição Sp1/metabolismo
18.
Anal Chem ; 91(15): 9724-9731, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31283184

RESUMO

In the past decade, tandem mass spectrometry (MS/MS)-based bottom-up proteomics has become the method of choice for analyzing post-translational modifications (PTMs) in complex mixtures. The key to the identification of the PTM-containing peptides and localization of the PTM-modified residues is to measure the similarities between the theoretical spectra and the experimental ones. An accurate prediction of the theoretical MS/MS spectra of the modified peptides will improve the similarity measurement. Here, we proposed the deep-learning-based pDeep2 model for PTMs. We used the transfer learning technique to train pDeep2, facilitating the training with a limited scale of benchmark PTM data. Using the public synthetic PTM data sets, including the synthetic phosphopeptides and 21 synthetic PTMs from ProteomeTools, we showed that the model trained by transfer learning was accurate (>80% Pearson correlation coefficients were higher than 0.9), and was significantly better than the models trained without transfer learning. We also showed that accurate prediction of the fragment ion intensities of the PTM neutral loss, for example, the phosphoric acid loss (-98 Da) of the phosphopeptide, will improve the discriminating power to distinguish the true phosphorylated residue from its adjacent candidate sites. pDeep2 is available at https://github.com/pFindStudio/pDeep/tree/master/pDeep2 .

19.
Biomacromolecules ; 20(9): 3340-3351, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31356057

RESUMO

Thermoresponsive hydrogels are used for an array of biomedical applications. Lower critical solution temperature-type hydrogels have been observed in nature and extensively studied in comparison to upper critical solution temperature (UCST)-type hydrogels. Of the limited protein-based UCST-type hydrogels reported, none have been composed of a single coiled-coil domain. Here, we describe a biosynthesized homopentameric coiled-coil protein capable of demonstrating a UCST. Microscopy and structural analysis reveal that the hydrogel is stabilized by molecular entanglement of protein nanofibers, creating a porous matrix capable of binding the small hydrophobic molecule, curcumin. Curcumin binding increases the α-helical structure, fiber entanglement, mechanical integrity, and thermostability, resulting in sustained drug release at physiological temperature. This work provides the first example of a thermoresponsive hydrogel comprised of a single coiled-coil protein domain that can be used as a vehicle for sustained release and, by demonstrating UCST-type behavior, shows promise in forging a relationship between coiled-coil protein-phase behavior and that of synthetic polymer systems.


Assuntos
Portadores de Fármacos/química , Hidrogéis/química , Polímeros/química , Proteínas/química , Preparações de Ação Retardada/química , Portadores de Fármacos/síntese química , Hidrogéis/síntese química , Interações Hidrofóbicas e Hidrofílicas , Domínios Proteicos/genética , Engenharia de Proteínas , Temperatura
20.
FEBS J ; 286(21): 4215-4231, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31199573

RESUMO

Cytochrome P450 1A1 (CYP1A1) is abundant in the kidney, liver, and intestine and is involved in the phase I metabolism of numerous endogenous and exogenous compounds. Therefore, exploring the regulatory mechanism of its basal expression in humans is particularly important to understand the bioactivation of several procarcinogens to their carcinogenic derivatives. Site-specific mutagenesis and deletion of the transcription factor binding site determined the core cis-acting elements in the human CYP1A1 proximal and distal promoter regions. The proximal promoter region [overlapping xenobiotic-responsive element (XRE) and GC box sequences] determined the basal expression of CYP1A1. In human hepatocellular carcinoma cells (HepG2) with aryl hydrocarbon receptor (AhR) or specificity protein 1 (Sp1) knockdown, we confirmed that AhR and Sp1 are involved in basal CYP1A1 expression. In HepG2 cells overexpressing either AhR or Sp1, AhR determined the proximal transactivation of basal CYP1A1 expression. Via DNA affinity precipitation assays and ChIP, we found that AhR bound to the promoter and recruited Sp1 to transactivate CYP1A1 expression. The coordinated interaction between Sp1 and AhR was identified to be DNA mediated. Our work revealed a basal regulatory mechanism of an interesting human gene by which AhR interacts with Sp1 through DNA and recruits Sp1 to regulate basal CYP1A1 expression.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Citocromo P-450 CYP1A1/genética , Neoplasias/genética , Receptores de Hidrocarboneto Arílico/genética , Fator de Transcrição Sp1/genética , Carcinógenos/toxicidade , Regulação da Expressão Gênica/genética , Células Hep G2 , Humanos , Mucosa Intestinal/metabolismo , Rim/metabolismo , Fígado/metabolismo , Desentoxicação Metabólica Fase I/genética , Neoplasias/induzido quimicamente , Neoplasias/patologia , Regiões Promotoras Genéticas , Ligação Proteica/genética , Ativação Transcricional/genética
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