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1.
PLoS Genet ; 18(10): e1010366, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36288387

RESUMO

BACKGROUND: Bladder cancer (BCa) is one of the most prevalent malignancies globally. Previous study has reported the inhibitory effect of methyltransferase-like 14 (METTL14) on BCa tumorigenesis, but its role in the cell migration, invasion and epithelial-mesenchymal transition (EMT) in BCa remains unknown. MATERIALS AND METHODS: Quantitative real-time PCR (RT-qPCR) and western blot were applied to measure RNA and protein expression respectively. Cell migration, invasion and EMT were evaluated by wound healing, Transwell, and immunofluorescence (IF) assays as well as western blot of EMT-related proteins. In vivo experiments were performed to analyze metastasis of BCa. Mechanism investigation was also conducted to study METTL14-mediated regulation of BCa progression. RESULTS: METTL14 overexpression prohibits BCa cell migration, invasion in vitro and tumor metastasis in vivo. METTL14 stabilizes USP38 mRNA by inducing N6-methyladenosine (m6A) modification and enhances USP38 mRNA stability in YTHDF2-dependent manner. METTL14 represses BCa cell migration, invasion and EMT via USP38. Additionally, miR-3165 inhibits METTL14 expression to promote BCa progression. CONCLUSIONS: Our study demonstrated that METTL14 suppresses BCa progression and forms a feedback loop with USP38. In addition, miR-3165 down-regulates METTL14 expression to promote BCa progression. The findings may provide novel insight into the underlying mechanism of METTL14 in BCa progression.


Assuntos
MicroRNAs , Neoplasias da Bexiga Urinária , Humanos , Transição Epitelial-Mesenquimal/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Retroalimentação , Linhagem Celular Tumoral , Movimento Celular/genética , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro , Metiltransferases/genética , Metiltransferases/metabolismo , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/farmacologia
2.
Biochem Biophys Res Commun ; 697: 149547, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38245926

RESUMO

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the µ-opioid (MOR) and sigma-1 (σ1R) receptors are reported. Compound 23 exhibited good affinity to σ1R (Ki = 44.7 ± 7.05 nM) and high selectivity to σ2R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED50 = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED50 = 5.23 mg/kg)). We obtained new dual ligands that might serve as starting points for preparing targeted tools. Furthermore, 23 may be a useful chemical probe for understanding more fully analgesic effects associated with MOR agonism and σ1R antagonism.


Assuntos
Amidas , Receptores sigma , Animais , Amidas/farmacologia , Amidas/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Ligantes , Receptores Opioides mu
3.
J Sleep Res ; : e14264, 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853286

RESUMO

Insufficient sleep can significantly affect vigilance and increase slow-wave electroencephalographic power as homeostatic sleep pressure accumulates. Phase-amplitude coupling is involved in regulating the spatiotemporal integration of physiological processes. This study aimed to examine the functional associations of resting-state electroencephalographic power and delta/theta-gamma phase-amplitude coupling from the prefrontal cortex (PFC) to posterior regions with vigilance performance after sleep deprivation. Forty-six healthy adults underwent 24-hr sleep deprivation with resting-state electroencephalographic recordings, and vigilant attention was measured using the Psychomotor Vigilance Task. Power spectral and phase-amplitude coupling analyses were conducted, and correlation analysis was utilized to reveal the relationship between electroencephalographic patterns and changes in vigilance resulting from sleep deprivation. Sleep deprivation significantly declined vigilance performance, accompanied by increased resting-state electroencephalographic power in all bands and delta/theta-gamma phase-amplitude coupling. The increased theta activity in centro-parieto-occipital areas significantly correlated with decreased mean and slowest response speed. Conversely, the increased delta-low gamma and theta-high gamma phase-amplitude couplings negatively correlated with the deceleration of the fastest Psychomotor Vigilance Task reaction times. These findings suggest that sleep deprivation affects vigilance by altering electroencephalographic spectral power and information communication across frequency bands in different brain regions. The distinct effects of increased theta power and delta/theta-gamma phase-amplitude coupling might reflect the impairment and compensation of sleep deprivation on vigilance performance, respectively.

4.
J Sleep Res ; 32(5): e13890, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-36948509

RESUMO

Vigilance is highly sensitive to the time-of-day effect and goes through the daytime trough during the period of the post-noon dip. A midday nap could maintain individuals' vigilance at an optimal level. Thus, homeostatic sleep pressure is one of the main reasons for the post-noon dip in daytime vigilance. The current study focussed on the role of homeostatic sleep pressure in the diurnal variation of vigilance performance with normal circadian rhythms and the corresponding neural basis. With 34 healthy adults, we recorded the resting-state electroencephalogram activities and the following vigilance performance measured by psychomotor vigilance test in the morning, the no-nap mid afternoon, and the nap mid afternoon. The circadian process was controlled by measuring vigilance and resting-state electroencephalogram activities at the same time point in the nap and no-nap conditions. Homeostatic sleep pressure accumulated from morning to mid afternoon induced the declined vigilance performance and a global increase in resting-state delta, theta, alpha, and beta1 bands power, and a local increase in beta2 band power in the central region. Furthermore, the more the spontaneous beta2 power increased, the less vigilance declined from morning to mid afternoon. The current findings suggest that homeostatic sleep pressure increased cortical excitability but decreased cortical communication efficiency from morning to mid afternoon. In addition, the activity of the high beta waves probably reflected the compensatory effort to counteract the negative impact of the low arousal state on the following vigilance task by performing more action preparation in the no-nap afternoon.


Assuntos
Sono , Vigília , Adulto , Humanos , Nível de Alerta , Ritmo Circadiano , Eletroencefalografia , Desempenho Psicomotor
5.
Analyst ; 148(3): 643-653, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36621928

RESUMO

Light-emitting diodes (LEDs), particularly in the blue waveform range, are regarded as a major source of circadian rhythm dysregulation. A circadian rhythm dysregulation induced by blue LEDs is associated with non-alcoholic fatty liver disease (NAFLD). Hepatocellular accumulation of lipids is a key event in the early stages of NAFLD. Kupffer cells (KCs) have been reported to be lost in the early onset of NAFLD followed by an inflammatory reaction that alters the liver response to lipid overload. This study focused on the detection of the initial stages (subpathological stages) of LED light-triggered NAFLD. Mice were exposed to either blue or white LED irradiation for 44 weeks. Synchrotron radiation-based Fourier-transform infrared microspectroscopy (SR-FTIRM) and wax physisorption kinetic-Fourier transform infrared (WPK-FTIR) imaging were used to evaluate the ratio of lipid to protein and the glycosylation of glycoprotein, respectively. Immunohistopathological studies on KCs and circadian-related proteins were performed. Although liver biopsy showed normal pathology, an SR-FTIRM study revealed a high hepatic lipid-to-protein ratio after receiving LED illumination. The results of WPK-FTIR demonstrated that a high inflammation index was found in the high irradiance of the blue LED illumnation group. These groups showed a decrease in KC number and an increase in Bmal1 and Reverbα circadian protein expression. These findings provide explanations for the reduction of KCs without subsequent inflammation. A significant reduction of Per2 and Cry1 expression is correlated with the findings of WPK-FTIR imaging. WPK-FTIR is a sensitive method for detecting initiative stages of NAFLD induced by long-term blue LED illumination.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Análise de Fourier , Inflamação/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ceras , Luz
6.
Environ Sci Technol ; 57(21): 7938-7949, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37202343

RESUMO

Obesity is prevalent in rural areas of China, and there are inconsistent findings regarding the association between metal(loid) exposure and the risk of obesity. Abdominal obesity (AOB), which reflects visceral fat abnormity, is a crucial factor in studying obesity-related diseases. We conducted a study measuring 20 urinary metal(loid)s, 13 health indicators, and the waist circumference (WC) in 1849 participants from 10 rural areas of China to investigate their relationships. In the single exposure models, we found that urinary chromium (Cr) was significantly associated with the odds of having AOB [adjusted odds ratio (OR) = 1.81 (95% confidence interval (CI): 1.24, 2.60)]. In the mixture exposure models, urinary Cr consistently emerged as the top contributor to AOB, while the overall effect of mixed metal(loid)s was positive toward the odds of having AOB [adjusted OR: 1.33 (95% CI: 1.00, 1.77)], as revealed from the quantile g-computation model. After adjusting for the effects of other metal(loid)s, we found that the elevation of apolipoprotein B and systolic blood pressure significantly mediated the association between urinary Cr and the odds of having AOB by 9.7 and 19.4%, respectively. Our results suggest that exposure to metal(loid)s is a key factor contributing to the prevalence of AOB and WC gain in rural areas of China.


Assuntos
Metaloides , Metais Pesados , Humanos , Obesidade Abdominal/epidemiologia , Metais/análise , Obesidade/epidemiologia , Cromo , China/epidemiologia , Gordura Abdominal/química , Medição de Risco , Monitoramento Ambiental/métodos
7.
Small ; 18(10): e2105329, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35023622

RESUMO

Nonprecious group metal (NPGM)-based single atom catalysts (SACs) hold a great potential in electrocatalysis and dopant engineering has been extensively exploited to boost their catalytic activity, while the coordination environment of dopant, which also significantly affects the electronic structure of SACs, and consequently their electrocatalytic performance, have been largely ignored. Here, by adopting a precursor modulation strategy, the authors successfully synthesize single cobalt atom catalysts embedded in nitrogen-doped carbon, Co-N/C, with similar overall Co and N concentrations but different N types, that is, pyridinic N (NP ), graphitic N (NG ), and pyrrolic N (NPY ). Co-N/C with the Co-N4 moieties coordinated with NG displays far superior activity for oxygen reduction (ORR) and evolution reactions, and superior activity and stability in both zinc-air batteries and proton exchange membrane fuel cells. Density functional theory calculation indicates that coordinated N species in particular NG functions as electron donors to the Co core of Co-N4 active sites, leading to the downshift of d-band center of Co-N4 and weakening the binding energies of the intermediates on Co-N4 sites, thus, significantly promoting catalytic kinetics and thermodynamics for ORR in a full pH range condition.

8.
Molecules ; 27(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36431877

RESUMO

Developing an efficient fracturing fluid system is an enduring hot topic in the petrochemical industries, especially regarding the exploitation of limited oil. Biopolymers, especially polysaccharides (e.g., konjac gum, guar gum), are widely applied as fracturing fluids in fracturing as a result of their advantages. Herein, we propose an easy method of modifying konjac gum (KGM) using isopropanol, sodium hydroxide, and chloroacetic acid to obtain modified konjac glum (MKGM). The MKGM and KGM gels were also obtained by using the self-prepared organic titanium high-temperature stabilizer and organic borate cross-linker. The prepared MKGM was characterized by multiscale techniques, including attenuated total reflection Fourier transform infrared (ATR-FTIR), X-ray diffraction (XRD), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), and rheology properties. The ATR-FTIR results showed that the etherification modification reaction occurred as designed. The XRD results showed that the regularity of KGM was destroyed after modification. The TGA and DSC results showed that the thermal stability improved. Rheology measurements illustrated that the temperature and shear resistance of MKGM were better than those of KGM. The MKGM gel could be applied in fracturing fluid systems at a lower frequency through viscoelastic measurements.


Assuntos
Amorphophallus , Fraturas Ósseas , Biopolímeros , Reologia , Difração de Raios X
9.
Biochem Biophys Res Commun ; 546: 138-144, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33582556

RESUMO

Hepatic injury is common in patients who suffer from severe burns plus delayed resuscitation (B + DR). Stimulator of interferon genes (STING) is primarily expressed in Kupffer cells (KCs). We demonstrated that B + DR caused hepatic injury and oxidative stress. Reactive oxygen species (ROS) damage mitochondrial membranes in hepatocytes, leading to the release of mitochondrial DNA (mtDNA) into the hepatocyte cytosol and the circulation. The damaged hepatocytes then activate the mtDNA/STING pathway in KCs and trigger KCs polarization towards pro-inflammatory phenotype. SS-31 is a strong antioxidant that specifically concentrates in the inner mitochondrial membrane. SS-31 prevented hepatic injury by neutralizing ROS, inhibiting the release of mtDNA, protecting hepatocyte mitochondria, suppressing the activation of the mtDNA/STING pathway and inhibiting KCs polarization into pro-inflammatory phenotype.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Queimaduras/complicações , DNA Mitocondrial/efeitos dos fármacos , Células de Kupffer/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/lesões , Proteínas de Membrana/metabolismo , Oligopeptídeos/farmacologia , Ressuscitação , Animais , DNA Mitocondrial/sangue , DNA Mitocondrial/metabolismo , Espaço Extracelular/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Células de Kupffer/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
10.
Bioorg Med Chem Lett ; 40: 127909, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705900

RESUMO

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.


Assuntos
Antipsicóticos/química , Cognição/efeitos dos fármacos , Piperidinas/química , Animais , Antipsicóticos/farmacologia , Comportamento Animal , Dopamina/química , Desenho de Fármacos , Humanos , Hiperprolactinemia/metabolismo , Camundongos , Modelos Animais , Movimento/efeitos dos fármacos , Piperidinas/farmacologia , Ligação Proteica , Receptores Histamínicos H3/química , Risperidona/farmacologia , Serotonina/química , Relação Estrutura-Atividade , Aumento de Peso
11.
Molecules ; 26(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919175

RESUMO

Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI2-RSV1·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI2-RSV1·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal.


Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Aripiprazol/química , Aripiprazol/farmacologia , Modelos Moleculares , Cristalização , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular , Estrutura Molecular , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
12.
Aust J Rural Health ; 29(4)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25819064

RESUMO

OBJECTIVE: To reveal the challenges of village doctors' survival and training in economically developed areas in eastern China. DESIGN: A field survey was used to assess the challenges of village doctors. SETTING: The study was conducted in Changzhou, Jiangsu province, which is an economically developed region in eastern China. PARTICIPANTS: The participants included 844 village doctors, 15 township hospital staff members and 6 health bureau leaders. RESULTS: The main challenges in Changzhou include an insufficient amount of village doctors, difficulties in obtaining professional qualification for village doctors, low salaries and benefits, and difficulties in recruitment. CONCLUSION: With increasing urbanisation in China, the gap between actual and expected income and social security has been increasing. Changes to training have influenced the stability of village doctor teams. Declining attachment of young people to their hometown village has contributed to recruitment difficulties.


Assuntos
Médicos , Serviços de Saúde Rural , Urbanização , China , Mão de Obra em Saúde , Humanos , Seleção de Pessoal , Médicos/provisão & distribuição , Salários e Benefícios , Inquéritos e Questionários
13.
Molecules ; 25(18)2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32911828

RESUMO

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.


Assuntos
Antipsicóticos/química , Técnicas de Química Sintética , Desenho de Fármacos , Flavonas/química , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Flavonas/síntese química , Flavonas/farmacologia , Ligantes , Receptores de Dopamina D2/química , Receptores de Serotonina/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade
14.
J Cell Sci ; 130(5): 1003-1015, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28082423

RESUMO

GFP-binding protein (or GBP) has been recently developed in various systems and organisms as an efficient tool to purify GFP-fusion proteins. Due to the high affinity between GBP and GFP or GFP variants, this GBP-based approach is also ideally suited to alter the localization of functional proteins in live cells. In order to facilitate the wide use of the GBP-targeting approach in the fission yeast Schizosaccharomyces pombe, we developed a set of pFA6a-, pJK148- and pUC119-based vectors containing GBP- or GBP-mCherry-coding sequences and variants of inducible nmt1 or constitutive adh1 promoters that result in different levels of expression. The GBP or GBP-mCherry fragments can serve as cassettes for N- or C-terminal genomic tagging of genes of interest. We illustrated the application of these vectors in the construction of yeast strains with Dma1 or Cdc7 tagged with GBP-mCherry and efficient targeting of Dma1- or Cdc7-GBP-mCherry to the spindle pole body by Sid4-GFP. This series of vectors should help to facilitate the application of the GBP-targeting approach in manipulating protein localization and the analysis of gene function in fission yeast, at the level of single genes, as well as at a systematic scale.


Assuntos
Técnicas Citológicas/métodos , Proteínas de Fluorescência Verde/metabolismo , Schizosaccharomyces/metabolismo , Sequência de Bases , Genes Reporter , Vetores Genéticos/metabolismo , Luciferases/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transporte Proteico , Proteínas Recombinantes de Fusão/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Corpos Polares do Fuso/metabolismo
15.
J Asian Nat Prod Res ; 18(8): 730-6, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26982483

RESUMO

Two new compounds, (Z,R)-1-phenylethylcinnamate (1) and (1R,2R,3R,6S)-pipoxide (2) were isolated from the aerial part of Piper hainanense, along with 12 known compounds, including nine benzene derivatives (4-11), one isobutylamide (12), and two polyoxygenated cyclohexene derivatives (13-14). Their structures were elucidated on the basis of the HRESIMS, 1D and 2D NMR spectroscopic analyses, and ECD in cases of 2 and 3. The absolute configuration of ellipeiopsol B (3) was determined for the first time. All these compounds 1-14 were reported from the titled plant for the first time. Most of the isolates were tested for their cytotoxicities against five human cancer cell lines. Four of which, 2, 3, 9, 14 showed moderate bioactivities. Among them, the new compound 2 showed potential cytotoxicity against SMMC-7721, MCF-7, and SW-480 with IC50 values of 9.7, 15.0, and 13.2 µM, respectively.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Cicloexenos/isolamento & purificação , Cicloexenos/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Piper/química , Antineoplásicos Fitogênicos/química , Cinamatos/química , Cicloexenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Triterpenos/química
16.
Theor Biol Med Model ; 12: 14, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26246000

RESUMO

BACKGROUND: A single-chain bispecific antibody (scBsAb; an engineered antibody), has promising clinical applications. Nonetheless, the effect of different interchain linkers on its activity is poorly understood. METHODS: Gene synthesis was used to splice the anti-γ-seminoprotein single-chain antibody (anti-γ-Sm scFv) gene with the anti-CD3 single-chain antibody (anti-CD3 scFv) gene via different interchain peptide linkers. The Phyre2 software was used to predict spatial configuration of different scBsAbs. Eukaryotic expression vectors carrying scBsAbs were constructed by molecular cloning techniques and these plasmids were transfected into HeLa cells with liposomes. scBsAbs were purified by Ni(2+)-NTA agarose and analysed for antigen binding by an enzyme-linked immunosorbent assay (ELISA). Blood pharmacokinetics and inhibition of prostate tumour growth in nude mice were analysed in in vivo experiments. RESULTS: Bioinformatics analysis and prediction showed that none of the three linkers, Fc, 205C', and HSA, had a significant effect on protein folding of anti-γ-Sm scFv or anti-CD3 scFv. Nevertheless, the spatial structures of the three linkers were noticeably different. Anti-γ-Sm × anti-CD3 scBsAb with an Fc, 205C', or HSA linker was successfully constructed, and these antibodies had similar protein expression levels. ELISA showed that all the three scBsAbs bound to Jurkat cells and the LNCaP membrane antigen, although binding of (205C')scBsAb was weaker than that of the two parental scFvs (P < 0.05). In contrast, binding strength of (HSA)scBsAb and (Fc)scBsAb was close to that of the parental scFvs (P > 0.05). Pharmacokinetic analysis showed that the half-clearance time of the elimination phase (T(1/2ß)) for (HSA)scBsAb was the longest: up to 4.4 h. Compared with γ-Sm ScFv, the three scBsAbs all had a much stronger inhibitory effect on the growth of prostate cancer (P < 0.05), but there were no significant differences among the three scBsAbs (P > 0.05). CONCLUSIONS: HSA is the optimal linker for the anti-γ-Sm × anti-CD3 scBsAb and may improve antigen-binding affinity of antibodies and prolong physiological retention time. Interchain linkers affect the function of scBsAbs; these effects may have important implications for construction of antibodies.


Assuntos
Anticorpos Antineoplásicos/imunologia , Especificidade de Anticorpos , Antígeno Prostático Específico/imunologia , Animais , Anticorpos Biespecíficos/biossíntese , Anticorpos Biespecíficos/genética , Anticorpos Biespecíficos/imunologia , Anticorpos Antineoplásicos/metabolismo , Biologia Computacional , Engenharia Genética , Vetores Genéticos , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Masculino , Camundongos , Camundongos Nus , Modelos Biológicos , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia
17.
Int J Health Plann Manage ; 30(1): E42-55, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24986628

RESUMO

As the most important public health service providers in rural China, village doctors are facing a new challenge of heavier workload resulting from the recent policy of public health service equalization. Studies on the shortage of village doctors, mainly based on the national statistics, have so far been very broad. This study conducted detailed field surveys to identify specific factors of and potential solutions to the shortage in village doctors. Eight hundred forty-four village doctors and 995 health decision makers and providers were surveyed through a questionnaire, and some of them were surveyed by in-depth face-to-face interviews and focus group interviews. Opinions on the shortage in village doctors and the potentially effective approaches to addressing the problem were sought. Some village doctors (51.3%) were at least 50 years old. Some village doctors (92.3%) did not want their children to become a village doctor, and the main reasons were "low salary" and "lack of social security". Village doctors felt that it was difficult to provide all the required public health services. Local residents indicated that they established good relationships with village doctors. Some health decision makers and providers (74.0%) thought that they needed more village doctors. The shortage in village doctors presents a major obstacle toward the realization of China's policy of public health service equalization. The aging of current village doctors exacerbates the problem. Policies and programs are needed to retain the current and attract new village doctors into the workforce. Separate measures are also needed to address disparities in socioeconomic circumstance from village to village.


Assuntos
Política de Saúde , Área Carente de Assistência Médica , Médicos/provisão & distribuição , Prática de Saúde Pública , Serviços de Saúde Rural , Adulto , Idoso , China , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Administração em Saúde Pública , Serviços de Saúde Rural/organização & administração , Inquéritos e Questionários , Recursos Humanos
18.
Molecules ; 19(7): 8965-80, 2014 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-24979401

RESUMO

Headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) was used to identify the volatile organic compounds (VOCs) of the different flower development stages of Cananga odorata for the evaluation of floral volatile polymorphism as a basis to determine the best time of harvest. Electronic nose results, coupled with discriminant factor analysis, suggested that emitted odors varied in different C. odorata flower development stages, including the bud, display-petal, initial-flowering, full-flowering, end-flowering, wilted-flower, and dried flower stages. The first two discriminant factors explained 97.52% of total system variance. Ninety-two compounds were detected over the flower life, and the mean Bray-Curtis similarity value was 52.45% among different flower development stages. A high level of volatile polymorphism was observed during flower development. The VOCs were largely grouped as hydrocarbons, esters, alcohols, aldehydes, phenols, acids, ketones, and ethers, and the main compound was ß-caryophyllene (15.05%-33.30%). Other identified compounds were ß-cubebene, D-germacrene, benzyl benzoate, and α-cubebene. Moreover, large numbers of VOCs were detected at intermediate times of flower development, and more hydrocarbons, esters, and alcohols were identified in the full-flowering stage. The full-flowering stage may be the most suitable period for C. odorata flower harvest.


Assuntos
Cananga/metabolismo , Flores/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Cananga/crescimento & desenvolvimento , Flores/crescimento & desenvolvimento , Cromatografia Gasosa-Espectrometria de Massas , Odorantes/análise , Análise de Componente Principal , Microextração em Fase Sólida , Compostos Orgânicos Voláteis/análise
19.
J Exp Psychol Hum Percept Perform ; 50(2): 193-215, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38376936

RESUMO

Previous studies suggest that interference control may be unaffected by sleep deprivation based on the unchanged interference effects (reaction time [RT] differences between incongruent and congruent conditions), while ignoring the overall slower RTs after sleep deprivation. In the present study, we interpreted these results from a new angle using a variant of diffusion model, diffusion model for conflict tasks (DMC), and investigated whether and how interference control is affected by sleep deprivation. Mathematical derivations and model simulations showed that unchanged task-irrelevant information processing (i.e., unaffected interference control) may not lead to the observed unchanged interference effects when considering the overall slower RTs after sleep deprivation (due to either decreased drift rate of task-relevant information or increased decision boundary). Therefore, the unchanged interference effects do not necessarily indicate unchanged interference control. We then conducted a Simon task following one night of sleep deprivation or normal sleep, and fitted the DMC to the data. Experimental results showed that the Simon effect was reversed when most of the trials were incongruent, indicating that participants used learned spatially incompatible stimulus-response associations to predict responses. However, the Simon effects in both mean RTs and RT distributions were not significantly modulated by sleep deprivation. Model fits showed that the drift rate of task-relevant information decreased and the time-to-peak of task-irrelevant activation increased after sleep deprivation. These results suggest that central information processing was degraded after sleep loss, and most importantly, task-irrelevant activation increased after sleep deprivation as interference control was impaired. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Cognição , Privação do Sono , Humanos , Aprendizagem
20.
PhytoKeys ; 238: 85-94, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38361981

RESUMO

Pipermotuoense X.W.Qin, F.Su & C.Y.Hao, a new species of Piperaceae from Xizang, China, is described and illustrated in this paper. The new species resembles P.yinkiangense and P.anisotis, but it can be readily distinguished from the compared species by several characteristics. Gonophyll leaves are chartaceous and the leaf secondary vein count is 7-9, with the outermost pair being very weak when there are nine veins. Additionally, the apical pair arises 2-4 cm above the base and the leaf base is asymmetrical, with bilateral petioles that cling and heal together. Pistillate floral bracts are sessile, with 3, 4 or 5 stigmas. The description of the new species includes photographs, detailed descriptions, notes on etymology, distribution and habitat, as well as comparisons with morphologically similar species.

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