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1.
Protein Expr Purif ; 216: 106430, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38184160

RESUMO

Pq3-O-UGT2, derived from Panax quinquefolius, functions as a ginsenoside glucosyltransferase, utilizing UDP-glucose (UDPG) as the sugar donor to catalyze the glycosylation of Rh2 and F2. An essential step in comprehending its catalytic mechanism involves structural analysis. In preparation for structural analysis, we expressed Pq3-O-UGT2 in the Escherichia coli (E. coli) strain Rosetta (DE3). The recombinant Pq3-O-UGT2 was purified through Ni-NTA affinity purification, a two-step ion exchange chromatography, and subsequently size-exclusion chromatography (SEC). Notably, the purified Pq3-O-UGT2 showed substantial activity toward Rh2 and F2, catalyzing the formation of Rg3 and Rd, respectively. This activity was discernible within a pH range of 4.0-9.0 and temperature range of 30-55 °C, with optimal conditions observed at pH 7.0-8.0 and 37 °C. The catalytic efficiency of Pq3-O-UGT2 toward Rh2 and F2 was 31.43 s-1 mΜ-1 and 169.31 s-1 mΜ-1, respectively. We further crystalized Pq3-O-UGT2 in both its apo form and co-crystalized forms with UDPG, Rh2 and F2, respectively. High-quality crystals were obtained and X-ray diffraction data was collected for all co-crystalized samples. Analysis of the diffraction data revealed that the crystal of Pq3-O-UGT2 co-crystalized with UDP-Glc belonged to space group P1, while the other two crystals belonged to space group P212121. Together, this study has laid a robust foundation for subsequent structural analysis of Pq3-O-UGT2.


Assuntos
Ginsenosídeos , Panax , Ginsenosídeos/metabolismo , Glicosiltransferases , Uridina Difosfato Glucose , Panax/genética , Panax/química , Panax/metabolismo , Cristalização , Escherichia coli/genética , Escherichia coli/metabolismo
2.
Nephrol Dial Transplant ; 39(2): 251-263, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-37458807

RESUMO

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.


Assuntos
Falência Renal Crônica , Diálise Peritoneal , Peritonite , Humanos , Feminino , Estudos Prospectivos , Diálise Peritoneal/efeitos adversos , Diálise Renal/efeitos adversos , Hemoglobinas , Falência Renal Crônica/epidemiologia , Peritonite/etiologia , Estudos Retrospectivos
3.
Phys Chem Chem Phys ; 26(2): 1267-1273, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38105690

RESUMO

Exploring structural and component evolution remains a challenging scientific problem for nanoscience. We propose a novel approach called principle of minimization of structure matching polymerization (SMP) change to rapidly explore the global minimum structure on the potential energy surface (PES). The new method can map low-dimensional stable structures to high-dimensional local minima, and this will make it possible for us to study the growth mechanisms of nanoparticles. Some new lowest-energy structures were found by SMP methods for sulfuric acid (SA)-dimethylamine (DMA) systems relative to previous studies. Additionally, we found that the growth process of boron clusters is mainly that the small-size boron clusters are continuously added to large-size boron clusters by structure matching for Bn (n = 2-36) systems, Bm + Bk → Bn, where m + k = n and 1 ≤ k ≤ 3. The SMP approach can greatly improve the search efficiency of other unbiased global optimization algorithms, such as basin-hopping (BH) and genetic algorithm (GA), with an enhancement of up to 19- and 7-fold relative to traditional BH and GA algorithms for searching the global minima of Bn (n = 14-22) systems. The SMP approach is general and flexible and can be applied to different kinds of problems, such as material structure design, crystal structure prediction, and new drug generation.

4.
BMC Bioinformatics ; 23(1): 372, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36100897

RESUMO

BACKGROUND: The main focus of in silico drug repurposing, which is a promising area for using artificial intelligence in drug discovery, is the prediction of drug-disease relationships. Although many computational models have been proposed recently, it is still difficult to reliably predict drug-disease associations from a variety of sources of data. RESULTS: In order to identify potential drug-disease associations, this paper introduces a novel end-to-end model called Graph convolution network based on a multimodal attention mechanism (GCMM). In particular, GCMM incorporates known drug-disease relations, drug-drug chemical similarity, drug-drug therapeutic similarity, disease-disease semantic similarity, and disease-disease target-based similarity into a heterogeneous network. A Graph Convolution Network encoder is used to learn how diseases and drugs are embedded in various perspectives. Additionally, GCMM can enhance performance by applying a multimodal attention layer to assign various levels of value to various features and the inputting of multi-source information. CONCLUSION: 5 fold cross-validation evaluations show that the GCMM outperforms four recently proposed deep-learning models on the majority of the criteria. It shows that GCMM can predict drug-disease relationships reliably and suggests improvement in the desired metrics. Hyper-parameter analysis and exploratory ablation experiments are also provided to demonstrate the necessity of each module of the model and the highest possible level of prediction performance. Additionally, a case study on Alzheimer's disease (AD). Four of the five medications indicated by GCMM to have the highest potential correlation coefficient with AD have been demonstrated through literature or experimental research, demonstrating the viability of GCMM. All of these results imply that GCMM can provide a strong and effective tool for drug development and repositioning.


Assuntos
Inteligência Artificial , Reposicionamento de Medicamentos , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Semântica
5.
Am J Nephrol ; 53(8-9): 663-674, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35977460

RESUMO

INTRODUCTION: Telemedicine (TM) has shown to provide potential benefits on clinical outcomes in patients with chronic kidney disease but limited evidences published in the peritoneal dialysis (PD) population. This study aimed to explore the long-term effects of TM on the mortality and technique failure. METHODS: The Peritoneal Dialysis Telemedicine-assisted Platform Cohort Study (PDTAP Study) was conducted prospectively in 27 hospitals in China since 2016. Patient and practice data were collected through the doctor-end of the TM app (Manburs) for all participants. TM including self-monitoring records, on-line education materials, and real-time physician-patient contact was only performed for the patient-end users of the Manburs. The primary outcome was all-cause mortality. The secondary outcomes were cause-specific mortality and all-cause and cause-specific permanent transfer to hemodialysis. RESULTS: A total of 7,539 PD patients were enrolled between June 2016 and April 2019, with follow-up till December 2020. Patients were divided into two cohorts: TM group (39.1%) and non-TM group (60.9%). A propensity score was used to create 2,160 matched pairs in which the baseline covariates were well-balanced. There were significantly lower risks of all-cause mortality (HR 0.59 [0.51, 0.67], p < 0.001), CVD mortality (HR 0.59 [0.49, 0.70], p < 0.001), all-cause transfer to hemodialysis (0.57 [0.48, 0.67], p < 0.001), transfer to hemodialysis from PD-related infection (0.67 [0.51, 0.88], p = 0.003), severe fluid overload (0.40 [0.30, 0.55], p < 0.001), inadequate solute clearance (0.49 [0.26, 0.92], p = 0.026), and catheter-related noninfectious complications (0.41 [0.17, 0.97], p = 0.041) in the TM group compared with the non-TM group. CONCLUSION: This study indicated real-world associations between TM usage and reduction in patient survival and technique survival through a multicenter prospective cohort.


Assuntos
Falência Renal Crônica , Diálise Peritoneal , Peritonite , Telemedicina , Humanos , Falência Renal Crônica/epidemiologia , Estudos de Coortes , Estudos Prospectivos , Diálise Peritoneal/métodos , Peritonite/epidemiologia , Peritonite/etiologia , Estudos Retrospectivos
6.
Phys Chem Chem Phys ; 24(45): 27908-27914, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36367290

RESUMO

Atmospheric aerosols have a significant influence on climate change through their effect on the cloud lifetime and the radiative balance of the Earth's atmosphere. Despite its importance, the mechanism of aerosol nucleation is still poorly understood. Based on the low-energy structure of cluster molecules, quantum chemical (QC) computations can help us to directly calculate the formation mechanism of atmospheric clusters and formation rates at the molecular level. However, deciphering the formation mechanism of pre-nucleated clusters, especially those close to the critical size (∼1.7 nm), remains extremely challenging because many millions of configuration spaces might need to be explored to find the low-energy structure. We present a new idea that establishes a comprehensive experimental and computational hybrid calculation protocol to integrate experimental data, isomer distributions, hydrogen bond interactions, and interaction sites for exploring the configuration spaces and clarifying the nucleation mechanism of acid-base clusters, whose maximum size can exceed 1.7 nm. This protocol can effectively and accurately explore the configuration space of complex large nucleation clusters on the potential energy surface (PES). The consistency of the cluster concentration and the formation rate between the experiment and the in situ measurement is much better than that of the previous studies and proves its accuracy. In addition, we found that malic acid (MA) can enhance sulfuric acid-dimethylamine (SA-DMA)-based particle formation rates in the atmospheric boundary layer, for example, in Shanghai and Beijing in the summer, with an enhancement of up to 700- and 135-fold, respectively. The enhancement in atmospheric particle formation by MA is critical for new particle formation in the boundary layer with relatively low SA and DMA concentrations and at high temperature. This model greatly improves our understanding of the complex aerosol nucleation mechanism of large-scale multicomponent cluster molecules.

7.
Phys Chem Chem Phys ; 24(45): 28047-28054, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36377512

RESUMO

Mass spectrometry measurements coupled with classical molecular dynamics (MD) simulations have been conducted in recent years to understand the final stage of ion formation in electrospray ionization (ESI). Here, to characterize the ion formation mechanism in the recently developed droplet-assisted ionization (DAI) source, MD simulations with various conditions (solute number, temperature, ions, composition) were performed to help explain DAI-based measurements. The specific binding ability of cortisone with preformed ions (ions of sodium, cesium and iodide) in evaporating nanodroplets makes the ion formation process characteristic of both the ion evaporation and charge residue models (IEM and CRM, respectively). Most preformed ions are ejected with dozens of solvent molecules to form gas-phase ions by IEM, while clusters of one or more cortisone molecules with one or more preformed ions remain in the evaporating droplet to form gas-phase ions by CRM. As the ratio of cortisone molecules to preformed ions increases, the number of preformed ions held in the droplet without ejection by the IEM increases. In other words, increasing the molecular solute to preformed ion ratio in the droplet increases the fraction of gas-phase ions formed by CRM relative to IEM. The increase in CRM relative to IEM is accompanied by an increase in the calculated activation energy barrier, which can explain the activation energy measurements by DAI, where droplets without preformed ions exhibit higher activation energies for gas-phase ion formation than droplets containing large numbers of preformed ions.


Assuntos
Cortisona , Espectrometria de Massas por Ionização por Electrospray/métodos , Simulação de Dinâmica Molecular , Íons , Solventes/química , Soluções
8.
Phys Chem Chem Phys ; 24(38): 23540-23550, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36129069

RESUMO

Atmospheric new particle formation (NPF), which has been observed globally in clean and polluted environments, is an important source of boundary-layer aerosol particles and cloud condensation nuclei, but the fundamental mechanisms leading to multi-component aerosol formation have not been well understood. Here, we use experiments and quantum chemical calculations to better understand the involvement of carboxylic acids in initial NPF from gas phase mixtures of carboxylic acid, sulfuric acid (SA), dimethylamine, and water. A turbulent flow tube coupled to an ultrafine condensation particle counter with particle size magnifier has been set up to measure NPF. Experimental results show that pyruvic acid (PA), succinic acid (SUA), and malic acid (MA) can enhance sulfuric acid-dimethylamine nucleation in the order PA < SUA < MA with a greater enhancement observed at lower SA concentrations. Computational results indicate that the carboxylic and hydroxyl groups are related to the enhancement. This experiment-theory study shows the formation of multi-component aerosol particles and the role of the organic functional group, which may aid in understanding the role of organics in aerosol nucleation and growth in polluted areas, and help to choose organic molecules of specific structures for simulation.

9.
BMC Psychiatry ; 22(1): 321, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513799

RESUMO

BACKGROUND: The shared care pathway for ADHD is a program developed in Canada with two main strategies: (a) implement a shared care pathway between general practitioners (GPs) and specialists, and (b) step up or down care so that the patient is treated at the most appropriate level of care, depending on the complexity or outcome of their illness. The current study aims to identify the challenges and facilitators of implementing this program in a Chinese mental health service setting. METHODS: Two focus groups were conducted using semi-structured interviews with a total of 7 health care providers in Beijing. An adapted grounded theory methodology using open-ended, axial and selective coding was used for data analysis. RESULTS: We identified three main levels related to barriers and facilitators: (1) a sociocultural level of patients' and health care providers' perspectives; (2) a structural level related to internal and external organizational environments; (3) and the level of the intervention itself with its characteristics. The project is generally aligned with the mandates and goals of the health system, but two of the main obstacles are the varying qualifications of physicians in hospitals of different levels, implying different needs and flexible and adapted training programs, and the lack of appropriate patient referral systems between the different hospital levels. CONCLUSION: Our study highlights the importance of consultation to obtain a "lay of the land" for deciding on the implementation steps of an a priori well accepted model of care.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Pequim , Canadá , Grupos Focais , Pessoal de Saúde , Humanos , Pesquisa Qualitativa
10.
Ren Fail ; 44(1): 191-203, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35170385

RESUMO

Peritoneal fibrosis (PF) is the main reason leading to declining efficiency and ultrafiltration failure of peritoneum, which restricts the application of peritoneal dialysis (PD). We aimed to investigate the effects and mechanisms of miR-122-5p on the PF. Sprague-Dawley (SD) rats were infused with glucose-based standard PD fluid to establish PF model. HE staining was performed to evaluate the extent of PF. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH) were performed to measure the expression level of miR-122-5p. Western blot was used to test the expression of transforming growth factor (TGF)-ß1, platelet-derived growth factor (PDGF)-A, Fibronectin 1 (FN1), extracellular matrix protein 1 (ECM1), Smad5, α-smooth muscle actin (SMA), collagen type 1(COL-1), Vimentin, E-Cadherin, Wnt1, ß-catenin, p-ß-catenin, c-Myc, c-Jun, and Cyclin D1. Immunohistochemistry (IHC) staining was used to detect type I collagen alpha 1 (Col1α1), α-SMA, and E-Cadherin expression. We found PF was glucose concentration-dependently enhanced in peritoneum of PD rat. The PD rats showed increased miR-122-5p and decreased Smad5 expression. MiR-122-5p silencing improved PF and epithelial-mesenchymal transition (EMT) process in PD rats. MiR-122-5p silencing attenuated the activity of the Wnt/ß-catenin signaling pathway. Importantly, dual-luciferase reporter assay showed Smad5 was a target gene of miR-122-5p. Smad5 overexpression significantly reversed the increases of PF and EMT progression induced by miR-122-5p overexpression. Moreover, miR-122-5p mimic activated Wnt/ß-catenin activity, which was blocked by Smad5 overexpression. Overall, present results demonstrated that miR-122-5p overexpression showed a deterioration effect on PD-related PF by targeting Smad5 to activate Wnt/ß-catenin pathway.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , MicroRNAs/metabolismo , Fibrose Peritoneal/metabolismo , Proteína Smad5/metabolismo , Animais , Caderinas/metabolismo , Humanos , Hibridização in Situ Fluorescente , Modelos Animais , Diálise Peritoneal/efeitos adversos , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Vimentina/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
11.
J Integr Plant Biol ; 64(9): 1739-1754, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35731022

RESUMO

The ginsenoside Rg3 found in Panax species has extensive pharmacological properties, in particular anti-cancer effects. However, its natural yield in Panax plants is limited. Here, we report a multi-modular strategy to improve yields of Rg3 in a Panax ginseng chassis, combining engineering of triterpene metabolism and overexpression of a lignin biosynthesis gene, phenylalanine ammonia lyase (PAL). We first performed semi-rational design and site mutagenesis to improve the enzymatic efficiency of Pq3-O-UGT2, a glycosyltransferase that directly catalyzes the biosynthesis of Rg3 from Rh2 . Next, we used clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing to knock down the branch pathway of protopanaxatriol-type ginsenoside biosynthesis to enhance the metabolic flux of the protopanaxadiol-type ginsenoside Rg3 . Overexpression of PAL accelerated the formation of the xylem structure, significantly improving ginsenoside Rg3 accumulation (to 6.19-fold higher than in the control). We combined overexpression of the ginsenoside aglycon synthetic genes squalene epoxidase, Pq3-O-UGT2, and PAL with CRISPR/Cas9-based knockdown of CYP716A53v2 to improve ginsenoside Rg3 accumulation. Finally, we produced ginsenoside Rg3 at a yield of 83.6 mg/L in a shake flask (7.0 mg/g dry weight, 21.12-fold higher than with wild-type cultures). The high-production system established in this study could be a potential platform to produce the ginsenoside Rg3 commercially for pharmaceutical use.


Assuntos
Ginsenosídeos , Panax , Ginsenosídeos/metabolismo , Lignina/metabolismo , Panax/química , Panax/genética , Panax/metabolismo , Fenilalanina Amônia-Liase/genética , Fenilalanina Amônia-Liase/metabolismo
12.
Water Sci Technol ; 83(3): 515-531, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33600358

RESUMO

Quorum sensing (QS) is a communication mode between microorganisms to regulate bacteria ecological relations and physiological behaviors, thus achieve the physiological function that single bacteria cannot complete. This phenomenon plays important roles in the formation of biofilm and granular sludge, and may be related to enhancement of some functional bacteria activity in wastewater treatment systems. There is a need to better understand bacterial QS in engineered reactors, and to assess how designs and operations might improve the removal efficiency. This article reviewed the recent advances of QS in several environmental systems and mainly analyzed the regulation mechanism of QS-based strategies for biofilm, granular sludge, functional bacteria, and biofouling control. The co-existences of multiple signal molecules in wastewater treatment (WWT) processes were also summarized, which provide basis for the future research on the QS mechanism of multiple signal molecules' interaction in WWT. This review would present some prospects and suggestions which are of practical significance for further application.


Assuntos
Percepção de Quorum , Purificação da Água , Biofilmes , Esgotos , Transdução de Sinais
13.
Int J Cancer ; 145(3): 842-856, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30720865

RESUMO

Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let-7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF-7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF-7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer-regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , RNA Longo não Codificante/genética , Tamoxifeno/farmacologia , Animais , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/fisiologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fase S
14.
BMC Cancer ; 19(1): 1128, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752753

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth-most common malignancy worldwide. Multiple previous studies have assessed the relationship between TM6SF2 gene polymorphism and the risk of developing HCC, with discrepant conclusions reached. To assess the association of TM6SF2 rs58542926 T/C gene polymorphism with liver cancer, we performed the current meta-analysis. METHODS: This study queried the MEDLINE, PubMed, EMBASE, and CENTRAL databases from inception to April 2019. Case-control studies assessing the relationship between TM6SF2 rs5854292 locus polymorphism and liver cancer were selected according to inclusion and exclusion criteria. The Stata 12.0 software was employed for data analysis. RESULTS: A total of 5 articles, encompassing 6873 patients, met inclusion criteria and were included in the meta-analysis. Statistical analysis showed that the TM6SF2 gene polymorphism was significantly associated with liver cancer in the allele contrast, dominant, recessive and over dominant models (T vs C, OR = 1.621, 95%CI 1.379-1.905; CT + TT vs CC. OR = 1.541, 95%CI 1.351-1.758; TT vs CT + CC, OR = 2.897, 95%CI 1.690-4.966; CC + TT vs TC, OR = 0.693, 95%CI 0.576-0.834). The Egger's test revealed no significant publication bias. CONCLUSION: The present findings suggest a significant association of TM6SF2 gene polymorphism with HCC risk in the entire population studied.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos
15.
J Phys Chem A ; 123(25): 5367-5377, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31199633

RESUMO

New particle formation (NPF) by gas-particle conversion is the main source of atmospheric aerosols. Highly oxygenated organic molecules (HOMs) and sulfuric acid (SA) are important NPF participants. 2-Methylglyceric acid (MGA), a kind of HOMs, is a tracer of isoprene-derived secondary organic aerosols. The nucleation mechanisms of MGA with SA were studied using density functional theory and atmospheric cluster dynamics simulation in this study, along with that of MGA with methanesulfonic acid (MSA) as a comparison. Our theoretical works indicate that the (MGA)(SA) and (MGA)(MSA) clusters are the most stable ones in the (MGA) i(SA) j ( i = 1-2, j = 1-2) and (MGA) i(MSA) j ( i = 1-2, j = 1-2) clusters, respectively. Both the formation rates of (MGA)(SA) and (MGA)(MSA) clusters are quite large and could have significant contributions to NPF. The results imply that the homomolecular nucleation of MGA is unlikely to occur in the atmosphere, and MGA and SA can effectively contribute to heteromolecular nucleation mainly in the form of heterodimers. MSA exhibits properties similar to SA in its ability to form clusters with MGA but is slightly weaker than SA.

16.
Cancer Sci ; 109(7): 2294-2301, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29777630

RESUMO

Breast cancer is one of the most common malignant diseases in women. Triple-negative breast cancer (TNBC) shows higher aggressiveness and recurrence rates than other subtypes, and there are no effective targets or tailored treatments for TNBC patients. Thus, finding effective prognostic markers for TNBC could help clinicians in their ability to care for their patients. We used tissue microarrays (TMAs) to detect microRNA-493 (miR-493) expression in breast cancer samples. A miRCURY LNA detection probe specific for miR-493 was used in in situ hybridization assays. Staining results were reviewed by two independent pathologists and classified as high or low expression of miR-493. Kaplan-Meier survival plots and multivariate Cox analysis were carried out to clarify the relationship between miR-493 and survival. In the Kaplan-Meier analysis, patients with high miR-493 expression had better disease-free survival than patients with low miR-493 expression. After adjusting for common clinicopathological factors in breast cancer, the expression level of miR-493 was still a significant prognostic factor in breast cancer. Further subtype analysis revealed that miR-493 expression levels were only significantly prognostic in TNBC patients. These results were validated in the Molecular Taxonomy of Breast Cancer International Consortium database for overall survival. We proved the prognostic role of miR-493 in TNBC by using one of the largest breast cancer TMAs available and validated it in a large public RNA sequencing database.


Assuntos
MicroRNAs/biossíntese , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Biomarcadores Tumorais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias de Mama Triplo Negativas/mortalidade
17.
Phys Chem Chem Phys ; 20(40): 25780-25791, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30283972

RESUMO

Atmospheric aerosols have a tremendous influence on visibility, climate, and human health. New particle formation (NPF) is a crucial source of atmospheric aerosols. At present, certain field observations and experiments have discovered the presence of 3-hydroxy-4,4-dimethylglutaric acid (HDMGA), which may participate in NPF events. However, the nucleation mechanism of HDMGA has not been clearly understood. In addition, dimethylamine (DMA) is an important precursor of nucleation. The nucleation mechanism involving HDMGA and DMA has not been studied. In this study, the most stable structures of (HDMGA)(H2O)n (n = 0-3) and (HDMGA)(DMA)(H2O)n (n = 0-3) were obtained by using M06-2X coupled with the 6-311++G(3df,3pd) basis set. The α-carboxyl group is directly attached to the amino group in all the most stable configurations. Proton transfer enhances the strength of a hydrogen bond, as well as promotes the generation of a global minimum structure. Temperature has a considerable influence on the distribution of isomers for (HDMGA)(DMA)(H2O)3 as compared to the other investigated clusters. The Gibbs free energy values reveal that most of the clusters can exist in NPF, except for (HDMGA)(H2O)1. The process of adding a cluster of (H2O)n more likely occurs in the atmosphere than gradually adding a single water molecule.

18.
J Phys Chem A ; 122(13): 3470-3479, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29547296

RESUMO

Ammonia and amines are important common trace atmospheric species that can enhance new particle formation (NPF) in the Earth's atmosphere. However, the synergistic effect of these two bases involving nucleation is still lacking. We studied the most stable geometric structures and thermodynamics of quaternary (NH3)(CH3NH2)(H2SO4) m(H2O) n ( m = 1-3, n = 0-4) clusters at the PW91PW91/6-311++G(3df,3pd) level of theory for the first time. We find that the proton transfer from H2SO4 molecule to CH3NH2 molecule is easier than to NH3 molecule in the free or hydrated H2SO4-base clusters, and thus leads to the stability. The energetically favorable formation of the (NH3)(CH3NH2)(H2SO4) m(H2O) n ( n = 0-4) clusters, by hydration or attachment of base or substitution of ammonia by methylamine at 298.15 K, indicate that ammonia and methylamine together could enhance the stabilization of small binary clusters. At low RH and an ambient temperature of 298.15 K, the concentration of total hydrated (NH3)(CH3NH2)(H2SO4)2 clusters could reach that of total hydrated (NH3)(H2SO4)2 clusters, which is the most stable ammonia-containing cluster. These results indicate that the synergistic effect of NH3 and CH3NH2 might be important in forming the initial cluster with sulfuric acid and subsequently growth process. In addition, the evaporation rates of (NH3)(CH3NH2)(H2SO4)(H2O), (NH3)(CH3NH2)(H2SO4)2 and (NH3)(CH3NH2)(H2SO4)3 clusters, three relative abundant clusters in (NH3)(CH3NH2)(H2SO4) m(H2O) n system, were calculated. We find the stability increases with the increasing number of H2SO4 molecules.

19.
Breast Cancer Res Treat ; 162(1): 39-48, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28093659

RESUMO

PURPOSE: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data. METHODS: We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment. RESULTS: The patients were divided into low, intermediate, and high MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P < 0.001). In hormone receptor-positive and human epidermal growth factor receptor-negative patients, the high MATH group showed a tendency toward a worse overall survival (P = 0.052); Furthermore, the TP53 mutation rate increased as MATH was elevated (P < 0.001), whereas CDH1 mutations were correlated with a lower level of MATH (P = 0.002). Several focal and arm-level SCNA events were more common in the high MATH group (P < 0.05), including Chr8q24 with only the MYC gene in the "peak" region. Similarly, high MATH was associated with gene set enrichment related to the MYC pathway and proliferation. CONCLUSION: Our integrative analysis reveals the clinical and genetic relevance of ITH in breast cancer. These results also suggest the origin and natural history of clonal evolution and intra-tumor genetic heterogeneity, which warrant further investigation.


Assuntos
Alelos , Neoplasias da Mama/genética , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Sequenciamento do Exoma , Adulto Jovem
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