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1.
Mol Med Rep ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-32016475

RESUMO

The present study aimed to clarify the protective effects of p­methoxyphenyl morpholino­phosphinodithioic acid (GYY4137), a water­soluble hydrogen sulfide­releasing molecule, on a rat model of intestinal ischemia­reperfusion (IIR). A total of 40 healthy male Sprague Dawley (SD) rats were randomly divided into four groups (n=10/group): Group A, a sham­surgery group; Group B, the IIR group; group C, rats with IIR that were administered an abdominal injection of low­dose GYY4137 (40 mg/kg); and group D, rats with IIR that were administered high­dose GYY4137 (80 mg/kg). Intestinal histomorphology was observed using hematoxylin and eosin staining, and the concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. Apoptotic index (AI) was determined by terminal deoxynucleotidyl­transferase­mediated dUTP nick end labeling. Reverse transcription­quantitative PCR analysis was performed to assess the expression levels of intestinal caspase­3, Bax and Bcl­2. Notably, disordered arrangement of intestinal villi and mucosal necrosis were detected in group B, which was substantially improved by GYY4137 treatment (groups C and D). MDA content (nmol/mg) was 2.83±0.36, 9.23±0.78, 4.97±0.45 and 3.51±1.05 nmol/mg in groups A, B, C and D, respectively. In addition, SOD concentration (U/mg) was 135.37±3.34, 76.45±1.39, 95.13±1.64 and 115.13±2.54 in groups A, B, C and D, respectively. Furthermore, AI in group B (21.73±1.17%) was markedly higher than that in group A (4.53±0.28%) and in the GYY4137 intervention groups (9.53±0.96 and 6.53±0.76% in groups C and D, respectively). Compared with in group A, the mRNA expression levels of Bax and caspase­3 were markedly higher in group B (P<0.05), whereas the expression of Bcl­2 was significantly lower (P<0.05). Furthermore, compared with in group B, Bcl­2 expression was higher, and Bax and caspase­3 expression was lower in groups C and D (P<0.05). In conclusion, GYY4137 may alleviate IIR­induced damage in SD rats.

2.
Curr Med Chem ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32003657

RESUMO

BACKGROUND: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. METHODS: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. RESULTS: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. CONCLUSION: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body's immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

3.
ACS Nano ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32017535

RESUMO

Biomedical device-associated infection (BAI) is a great challenge in modern clinical medicine. Therefore, developing efficient antibacterial materials is significantly important and meaningful for the improvement of medical treatment and people's health. In the present work, we developed a strategy of surface functionalization for multifunctional antibacterial applications. A functionalized polyurethane (PU, a widely used biomedical material for hernia repairing) surface (PU-Au-PEG) with inherent antifouling and photothermal bactericidal properties was readily prepared based on a near-infrared (NIR)-responsive organic/inorganic hybrid coating which consists of gold nanorods (Au NRs) and polyethylene glycol (PEG). The PU-Au-PEG showed a high efficiency to resist adhesion of bacteria and exhibited effective photothermal bactericidal properties under 808 nm NIR irradiation, especially against multidrug-resistant bacteria. Furthermore, the PU-Au-PEG could inhibit biofilm formation long term. The biocompatibility of PU-Au-PEG was also proved by cytotoxicity and hemolysis tests. The in vivo photothermal antibacterial properties were first verified by a subcutaneous implantation animal model. Then, the anti-infection performance in a clinical scenario was studied with an infected hernia model. The results of animal experiment studies demonstrated excellent in vivo anti-infection performances of PU-Au-PEG. The present work provides a facile and promising approach to develop multifunctional biomedical devices.

4.
J Appl Microbiol ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32027448

RESUMO

AIMS: The purpose of this study was to isolate Lactobacillus from gastrointestinal tract of healthy post-weaning piglets and investigate its synergistic antimicrobial and probiotic effects with ZnO nanoparticles (nZnO). METHODS AND RESULTS: Out of the 128 isolates, L. plantarum BLPL03 was selected based on its excellent acid and bile salt tolerance properties. L. plantarum BLPL03 was sensitive to ß-lactams, macrolides, amphenicols, and cephalosporins, whereas it displayed the steady resistance to aminoglycosides, tetracyclines, quinolones, and peptide antibiotics. In vitro analysis of antibacterial activities showed that L. plantarum BLPL03 inhibited the four common food-borne pathogenic bacteria including Escherichia coli O157:H7 CMCC44828, Salmonella typhimurium ATCC13311, Staphylococcus aureus CMCC26003, and Listeria monocytogenes CMCC54007 in synergy with nZnO. Furthermore, the quantitative polymerase chain reaction test demonstrated that the combined administration of L. plantarum BLPL03 fermentation liquor (LFL) and nZnO synergistically elevated the fecal number of Bifidobacterium by 73.19-fold, and reduced the two potential enteropathogenic bacteria Enterobacteriaceae and Clostridium perfringens in mice challenged with S. Typhimurium. Finally, dietary supplementation with low dose of nZnO (20 mg/kg) when combined with LFL administration enhanced final body weight, fur appearance and average daily gain, and decreased feed conversion ratio and diarrhea incidence in weaned piglets. The fecal Bifidobacterium and Lactobacillus of piglets were dramatically enhanced by 81.96- and 3.15-fold, respectively, after administration of a mixture of nZnO and LFL. Meanwhile, combination of nZnO with LFL resulted in low levels of Bacteroides, Enterococcus, and Enterobacteriaceae. CONCLUSIONS: A combination of nZnO and LFL exhibits potential health-benefit properties for the control of gut microbial composition by their synergistic antimicrobial and probiotic effects. SIGNIFICANCE AND IMPACT OF THE STUDY: This study may provide a potential nutritional strategy to improve performance and gut health of animals with gut microbiota disorders caused by pathogen infections and weanling, and so on.

5.
Nat Commun ; 11(1): 594, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001707

RESUMO

Activation of receptor tyrosine kinase (RTK) protein is frequently observed in malignant progression of gliomas. In this study, the crosstalk activation of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling pathways is demonstrated to contribute to temozolomide (TMZ) resistance, resulting in an unfavorable prognosis for patients with glioblastoma. To simultaneously mitigate EGFR and MET activation, a dual functionalized brain-targeting nanoinhibitor, BIP-MPC-NP, is developed by conjugating Inherbin3 and cMBP on the surface of NHS-PEG8-Mal modified MPC-nanoparticles. In the presence of BIP-MPC-NP, DNA damage repair is attenuated and TMZ sensitivity is enhanced via the down-regulation of E2F1 mediated by TTP in TMZ resistant glioma. In vivo magnetic resonance imaging (MRI) shows a significant repression in tumor growth and a prolonged survival of mice after injection of the BIP-MPC-NP and TMZ. These results demonstrate the promise of this nanoinhibitor as a feasible strategy overcoming TMZ resistance in glioma.

7.
Phys Chem Chem Phys ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32048669

RESUMO

It has long been a challenge in physics and chemistry to acquire a global picture of the energy landscape of a specific material, as well as the kinetic transformation process between configurations of interest. Here we have presented a comprehensive approach to deal with the structure transformation problem, along with the illustration of the energy landscape, as exemplified with the case of Au13. A configuration space based on interatomic distances was proposed and demonstrated to have a strong correlation between structure and energy, with application in structure analysis to screen for trial transition pathways. As several representative configurations and their transition pathways ascertained and by projecting on a plane, a visual two-dimensional contour map was sketched revealing the unique energy landscape of Au13. It shows that the 2D and 3D clusters form two funnels in the high-dimensional configuration space, with a transition pathway with a 0.976 eV barrier bridging them.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32054593

RESUMO

Extranodal natural killer/T cell lymphoma (ENKL), nasal type is a kind of rare disease with a low survival rate that primarily affects Asian and South American populations. Segmentation of ENKL lesions is crucial for clinical decision support and treatment planning. This paper is the first study on computer-aided diagnosis systems for the ENKL segmentation problem. We propose an automatic, coarse-to-fine approach for ENKL segmentation using adversarial networks. In the coarse stage, we extract the region of interest bounding the lesions utilizing a segmentation neural network. In the fine stage, we use an adversarial segmentation network and further introduce a multi-scale L1 loss function to drive the network to learn both global and local features. The generator and discriminator are alternately trained by backpropagation in an adversarial fashion in a min-max game. Furthermore, we present the first exploration of zone-based uncertainty estimates based on Monte Carlo dropout technique in the context of deep networks for medical image segmentation. Specifically, we propose the uncertainty criteria based on the lesion and the background, and then linearly normalize them to a specific interval. This is not only the crucial criterion for evaluating the superiority of the algorithm, but also permits subsequent optimization by engineers and revision by clinicians after quantitatively understanding the main source of uncertainty from the background or the lesion zone. Experimental results demonstrate that the proposed method is more effective and lesion-zone stable than state-of-the-art deep-learning based segmentation model.

9.
Mikrochim Acta ; 187(3): 166, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32055961

RESUMO

Doubly charged pH-responsive core/shell hydrogel nanoparticles with green fluorescence were prepared and were shown to be viable bioprobes for active targeting tumor tissue and imaging of cancer cells. Via emulsionfree copolymerization hydrogel nanoparticles as VANPs were prepared, the core of which was polystyrene (Ps) and the shell was comprised of strongly positive electrolyte (ar-vinylbenzyl)trimethylammonium (VBTAC) with weak negative electrolyte acrylic acid (AA). Through conventional amidation, the shell was conjugated with cell-specific folic acid (FA), denoted as VANPs-FA. Then, negatively charged sulfonated 9,10-distyrylanthracene derivatives (SDSA) based on aggregation induced emission (AIE), was binding tightly to positively charged VBTAC of VANPs-FA shell. The prepared double charged fluorescent core/shell hydrogel nanoparticles abbreviated as VANPs-FS, showed excitation/emission wavelengths at ~420/528 nm. Dynamic light scattering (DLS) measurements were performed to determine the size and surficial zeta potential of VANPs-FS. Under proper ratio of VBTAC to AA, the VANPs-FS was stable (~ 64.63 nm, -20.2 mV) at high pH (> 7), started to aggregate (~ 683.0 nm, -3.2 mV) at pH around 6, and can redispers at low pH (< 5). The MTT analysis proved that VANPs-FS had good biocompatibility and low cytotoxicity. The targeting effectiveness of VANPs-FS was confirmed by confocal laser scanning microscopy (CLSM). Graphical abstract Detailed synthetic route of VANPs-FS (top) and schematic cancer tumor-target aggregation of pH-sensitive VANPs-FS with enhanced retention and rapid cancer cell imaging (bottom).

10.
Brain Connect ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32056450

RESUMO

OBJECTIVE: Hierarchical organization of brain function has been an established concept in the neuroscience field for a long time, however, it has been rarely demonstrated how such hierarchical macroscale functional networks are actually organized in the human brain. In this study, to answer this question, we propose a novel methodology to provide an evidence of evidence on hierarchical organization of functional brain networks. METHOD: This paper introduces the Hybrid Spatiotemporal Deep Learning (HSDL), by jointly using Deep Belief Networks (DBN) and Deep LASSO to reveal the temporal hierarchical features and spatial hierarchical maps of brain networks based on the Human Connectome Project (HCP) 900 fMRI datasets. Briefly, the key idea of HSDL is to extract the weights between two adjacent layers of DBN, which are then treated as the hierarchical dictionaries for Deep LASSO to identify the corresponding hierarchical spatial maps. CONCLUSION: Our results demonstrate that both spatial and temporal aspects of dozens of functional networks exhibit multiscale properties that can be well characterized and interpreted based on existing computational tools and neuroscience knowledge. SIGNIFICANCE: Our proposed novel hybrid deep model is employed to provide the first insightful opportunity to reveal the potential hierarchical organization of time series and functional brain networks, using task-based fMRI signals of human brain.

11.
BMC Pediatr ; 20(1): 63, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041574

RESUMO

BACKGROUND: The mid-long term outcomes of posterior spinal fusion in pediatric neurofibromatosis type 1 (NF-1) patients are rarely reported, so does the effectiveness of itsorthopeidc maintenance function. This study aims to evaluate the mid-long term surgical outcomes of posterior only instrumented spinal fusion for early-onset scoliosis (EOS) in NF-1 patients. METHODS: A retrospective review was performed on a cohort of 10 NF-1 patients having EOS from 2008 to 2014 in our hospital, the age averaged at 7.8 years old when they underwent posterior only instrumented spinal fusion for their EOS. Both general clinical data and surgical specific data of the patients were collected and reviewed, and the dystrophic progression of EOS was evaluated during the follow-up. RESULTS: The average duration of follow-up was 54 months (24 to 88 months). All patients underwent posterior only instrumented spinal fusion at 1 stage. The primary curves of EOS were thoracic in 9 cases and 1 patient had lumbar scoliosis. Preoperative major curve was significantly corrected (from 66.1 to 31.1 degrees). However, the major curve deteriorated significantly to 40.1 degrees on average at the end of the follow-up. The T1-S1 distance increased 2.8 cm on average and kept increasing at a rate of 0.6 cm/year during the follow-up. CONCLUSIONS: Posterior only fusion surgery was not a good option to treat the EOS in NF-1 patients despite the relatively short segments involvement in the disease. The maintenance of orthopedic effect after treatment was not satisfactory.

12.
Exp Parasitol ; : 107843, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044321

RESUMO

The intracellular protozoan Toxoplasma gondii infects approximately one-third of the world's population as well as various animals, causing toxoplasmosis. However, there remains a need to define the functions of newly identified genes of T. gondii. In the present study, a novel molecule, immune mapped protein 1 of T. gondii (TgIMP1), was devitalized by CRISPR/Cas9 system to investigate the phenotypic changes of the parasite. We found that the virulence of ΔTgIMP1 knockout strain was reduced in comparison with wild-type GT1 tachyzoites, showing a statistically decreased plaque in HFF cells and a significantly prolonged survival period of mice (P < 0.05). Moreover, the data of phenotype analyses in vitro showed a different level of the intracellular proliferation and the subsequent egress between ΔTgIMP1 and wild-type GT1 strain (P < 0.05); while no statistically significant difference was detected during the process of attachment or invasion. These results suggested that TgIMP1 is closely associated with the intracellular proliferation of this parasite.

13.
Chin Med J (Engl) ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044816

RESUMO

BACKGROUND: Fever is the most common chief complaint of emergency patients. Early identification of patients at an increasing risk of death may avert adverse outcomes. The aim of this study was to establish an early prediction model of fatal adverse prognosis of fever patients by extracting key indicators using big data technology. METHODS: A retrospective study of patients' data was conducted using the Emergency Rescue Database of Chinese People's Liberation Army General Hospital. Patients were divided into the fatal adverse prognosis group and the good prognosis group. The commonly used clinical indicators were compared. Recursive feature elimination method was used to determine the optimal number of the included variables. In the training model, logistic regression, random forest, adaboost, and bagging were selected. We also collected the emergency room data from December 2018 to December 2019 with the same inclusion and exclusion criterion. The performance of the model was evaluated by accuracy, F1-score, precision, sensitivity, and the areas under receiver operator characteristic curves (ROC-AUC). RESULTS: The accuracy of logistic regression, decision tree, adaboost and bagging was 0.951, 0.928, 0.924, and 0.924, F1-scores were 0.938, 0.933, 0.930, and 0.930, the precision was 0.943, 0.938, 0.937, and 0.937, ROC-AUC were 0.808, 0.738, 0.736, and 0.885, respectively. ROC-AUC of ten-fold cross-validation in logistic and bagging models were 0.80 and 0.87, respectively. The top six coefficients and odds ratio (OR) values of the variables in the logistic regression were cardiac troponin T (CTnT) (coefficient = 0.346, OR = 1.413), temperature (T) (coefficient = 0.235, OR = 1.265), respiratory rate (RR) (coefficient= -0.206, OR = 0.814), serum kalium (K) (coefficient = 0.137, OR = 1.146), pulse oxygen saturation (SPO2) (coefficient = -0.101, OR = 0.904), and albumin (ALB) (coefficient = -0.043, OR = 0.958). The weights of the top six variables in the bagging model were: CTnT, RR, lactate dehydrogenase, serum amylase, heart rate, and systolic blood pressure. CONCLUSIONS: The main clinical indicators of concern included CTnT, RR, SPO2, T, ALB, and K. The bagging model and logistic regression model had better diagnostic performance comprehesively. Those may be conducive to the early identification of critical patients with fever by physicians.

14.
Fitoterapia ; 142: 104490, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017968

RESUMO

Privileged structures are widely used in the process of drug design, and provide an effective template in medicinal chemistry. Diarylheptanoids are a class of structurally distinctive compounds with a wide variety of bioactivity, raising keenly interest in the past decades. Turmeric is a golden spice from the rhizome of the plant Curcuma longa, used for food preparations and giving color since ancient times. Curcumin, obtained from turmeric, has showed widely biological abilities with low toxicity in recent studied. Thus, a spice originally common in the kitchen has recently broadened its application to the clinic. This review aims to highlight diarylheptanoid as a privileged scaffold in drug discovery. In this review, we summarized diverse biological and pharmacological effects of diarylheptanoids and explored the therapeutic application and development of diet based on their structure.

15.
Medicine (Baltimore) ; 99(5): e18341, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000355

RESUMO

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) has contributed to an increasing number of deaths and readmissions over the past few decades. Despite the appearance of standard treatments, including diuretics, ß-receptor blockers and angiotensin-converting enzyme inhibitor (ACEI), there are still a large number of patients who have progressive deterioration of heart function and, inevitably, end-stage heart failure. In recent years, new medications for treating chronic heart failure have been clinically applied, but there is controversy surrounding drug selection and whether patients with HFrEF benefit from these medications. Therefore, we aimed to compare and rank different new pharmacological treatments in patients with HFrEF. METHODS: We performed a network meta-analysis to identify both direct and indirect evidence from relevant studies. We searched MEDLINE, EMBASE, and PsycINFO through the OVID database and CENTRAL through the Cochrane Library for clinical randomized controlled trials investigating new pharmacological treatments in patients with HFrEF published up to September 30, 2018. We included trials of ivabradine, levosimendan, omega-3, tolvaptan, recombinant human B-type natriuretic peptide (rhBNP), isosorbide dinitrate and hydralazine (ISDN/HYD) and angiotensin-neprilysin inhibition (LCZ696). We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool. Based on these items, more than half of the entries were judged as having an overall low to moderate risk of bias; the remaining studies had a high or unclear risk of bias. The outcomes investigated were left ventricle ejection fraction (LVEF %), heart rate (HR) and serum level of B-type natriuretic peptide (BNP). We performed a random-effects network meta-analysis within a Bayesian framework. RESULTS: We deemed 32 trials to be eligible that included 3810 patients and 32 treatments. Overall, 32 (94.1%) trials had a low to moderate risk of bias, while 2 (5.9%) trials had a high risk of bias. The quality of the included studies was rated as low in regard to allocation concealment and blinding and high in regard to other domains according to the Cochrane tools. As for increasing LVEF%, levosimendan was better than placebo (-3.77 (-4.96, -2.43)) and was the best intervention for improving ventricle contraction. As for controlling HR, n3-PUFA was better than placebo (4.01 (-0.44, 8.48)) and was the best choice for regulating HR. As for decreasing BNP, omega-3 was better than placebo (941.99 (-47.48, 1952.89) and was the best therapy for improving ventricle wall tension. CONCLUSIONS: Our study confirmed the effectiveness of the included new pharmacological treatments for optimizing the structural performance and improving the cardiac function in the management of patients with HFrEF and recommended several interventions for clinical practice.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Teorema de Bayes , Humanos , Volume Sistólico
16.
Int J Infect Dis ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32004687

RESUMO

OBJECTIVE: To assess the immune effect of different types of hepatitis B vaccine (HepB) booster doses 2 to 32 years after primary immunization, explore the influencing factors, and offer guidance regarding the necessity and timing of boosters. METHODS: In total, 1163 participants who were born from 1986 to 2015, received the HepB full-course primary vaccination, were hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) negative, and had hepatitis B surface antibody (anti-HBs) <10 mIU/mL were enrolled. Individuals were randomly divided into two groups and received a booster dose of HepB. Venous blood samples were collected 30 days later and tested for anti-HBs. RESULTS: In total, 595 and 568 individuals received a single dose of HepB (CHO) and HepB (SC), respectively. Venous blood samples were obtained from 1079 vaccinees (CHO: 554, SC: 525). The seroconversion rates were 93.68% (519/554) and 86.67% (455/525) (p < 0.05), with geometric mean concentrations (GMCs) of 426.58 mIU/ml and 223.87 mIU/ml, respectively. This result indicated that BMI, smoking status, vaccine types of booster and prebooster anti-HBs concentration significantly influenced anti-HBs levels. Only BMI, prebooster anti-HBs concentrations and booster types were different between the anti-HBs positive and negative groups. CONCLUSIONS: Participants boostered with HepB (CHO) had a relatively higher seroconversion rate than those boostered with HepB (SC). The high seroconversion rates in the two groups suggested that the subjects remained protected despite low circulating antibodies, so there is currently no urgent need for booster immunization. Factors including BMI ≥ 25 and prebooster anti-HBs concentration < 2.5 mIU/mL, which contributed to lower responses to a booster dose, might indicate a greater risk of breakthrough infection.

17.
J Mol Cell Cardiol ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32006532

RESUMO

Hypertension is an independent risk factor for atrial fibrillation (AF), although its specific mechanisms remain unclear. Previous research has been focused on cyclic stretch, ignoring the role of high hydrostatic pressure. The present study aimed to explore the effect of high hydrostatic pressure stimulation on electrical remodeling in atrial myocytes and its potential signaling pathways. Experiments were performed on left atrial appendages from patients with chronic AF or sinus rhythm, spontaneously hypertensive rats (SHRs) treated with or without valsartan (10 mg/kg/day) and HL-1 cells were exposed to high hydrostatic pressure using a self-developed device. Whole-cell patch-clamp recordings and western blots demonstrated that the amplitudes of ICa,L, Ito, and IKur were reduced in AF patients with corresponding changes in protein expression. Angiotensin protein levels increased and Ang1-7 decreased, while focal adhesion kinase (FAK) and Src kinase were enhanced in atrial tissue from AF patients and SHRs. After rapid atrial pacing, AF inducibility in SHR was significantly higher, accompanied by a decrease in ICa,L, upregulation of Ito and IKur, and a shortened action potential duration. Angiotensin upregulation and FAK/Src activation in SHR were inhibited by angiotensin type 1 receptor inhibitor valsartan, thus, preventing electrical remodeling and reducing AF susceptibility. These results were verified in HL-1 cells treated with high hydrostatic pressure, and demonstrated that electrical remodeling regulated by the FAK-Src pathway could be modulated by valsartan. The present study indicated that high hydrostatic pressure stimulation increases AF susceptibility by activating the renin-angiotensin system and FAK-Src pathway in atrial myocytes.

18.
J Chromatogr A ; : 460948, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32059867

RESUMO

In this study, an online capillary electrophoresis (CE) based dual-enzyme (thrombin and factor Xa) co-immobilized microreactor (THR-FXa IMER) was constructed for studying enzyme kinetics and screening dual-target inhibitors against THR and FXa with the aid of the polydopamine/graphene oxide (PDA/GO) coating. Based on the developed THR-FXa IMER, the Michaelis-Menten constants (Km) of THR and FXa were calculated to be 187.26 and 48.80 µM, respectively. The inhibition constants (Ki) for two known inhibitors, argatroban and rivaroxaban, on THR and FXa were determined to be 14.73 and 0.41 nM, respectively. In addition, after 30 consecutive runs, the enzymes' activity was remained 98% of the initial immobilized activity for both THR and FXa, which shows that the constructed IMER has good stability and repeatability. Finally, the developed method was successfully applied to screen dual-target inhibitors against THR and FXa from 30 small molecular compounds. Among them, 10 compounds such as salvianolic acid C and epigallocatechin gallate (EGCG) have dual-enzyme inhibitory activity, and 2 compounds named saikosaponin A and oleuropein have single THR inhibitory activity, 5 compounds such as rosemary acid and salvianolic acid B have single FXa inhibitory activity. Finally, the molecular interactions between enzyme and potential inhibitors were further verified via the molecular docking, and a new compound with a theoretically good coagulation inhibition effect was designed by the scaffold hopping study. In summary, the developed THR-FXa IMER is a reliable method for screening THR and/or FXa inhibitors.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32030978

RESUMO

Developing discotic columnar liquid crystals (LCs) with both high electrical conductivity and strong luminescence remains a challenge, since the intracolumnar interdisc π-π stacking usually in ordered discotic columnar LCs is essential to generate charge transport pathways, but normally detrimental to light emissions. We here present a kind of tricyanotristyrylbenzene (TCS)-based quasi-discotic LCs upon bearing three wedge-shaped alkyl tails for addressing this issue. The resulted columnar materials displayed both high electrical conductivity and strong luminescence, especially for the ones stabilized by multivalent hydrogen-bonding interactions. Besides, an interesting thermochromic luminescence tuning behavior in a smooth manner was observed over a wide wavelength range for the hydrogen bond stabilized columnar LCs. This study will lead to the future design and application of new multifunctional optoelectronic materials by integrating excellent conductivity and luminescence tuning behaviors.

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