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1.
Artigo em Inglês | MEDLINE | ID: mdl-32396496

RESUMO

We have previously shown that systemic injection of exogenous erythropoietin-producing hepatocellular (EPH) A7-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose estradiol (E2) treatment, we investigated the association between EPHA7-ephrin (EFN) A5 signaling and E2-negative feedback. Various rat models (OVX, E2-treated OVX, and abarelix-treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. Efna5 was observed strongly expressed in the arcuate nucleus of the female rat using RNAscope in situ hybridization. Our results indicated that E2, combined with estrogen receptor (ER) α, but not ERß, inhibited Efna5 and gonadotrophin-releasing hormone 1 (Gnrh1) expression in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of Efna5 and Gnrh1 by E2, resulting in increased Efna5 and Gnrh1 expression in the hypothalamus, as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E2-negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.

2.
Nanoscale ; 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32393931

RESUMO

Mid-infrared (MIR) represents a crucial spectral region for applications in spectroscopy, sensing, imaging, security and industry screening, owing to the strong characteristic vibrational transitions of many important molecules. However, the current MIR compatible materials are fragile, hazardous, and costly, which hampers the performance of MIR devices. Here, we developed a versatile transmittance-based Kramers-Kronig method and obtained the optical properties of graphene oxide in the MIR region, unveiling its application potentials as a novel MIR compatible material. As an example, we demonstrated free-standing graphene oxide MIR polarizers with large extinction ratio (∼20 dB) and controllable working wavelength up to 25 µm, by using the low-cost and flexible direct laser writing technique. Our transmittance-based KK method offers a versatile approach to obtain the optical properties of novel atomic-scale low-dimensional materials in the less developed MIR region and opens up opportunities in high performing functional MIR devices.

3.
Opt Lett ; 45(9): 2584-2587, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32356822

RESUMO

Fabrication of high-aspect-ratio (HAR) micro/nanostructures by two-photon polymerization (TPP) has become a hot topic because of the advantages of ultra-high resolution and true 3D printing ability. However, the low efficiency caused by point-by-point scanning strategy limits its application. In this Letter, we propose a strategy for the rapid fabrication of HAR microstructures by combining TPP with an amplitude-phase optimized long depth of focus laser beam (LDFB). The optimization of the LDFB is implemented by modulating the amplitude and phase on a phase-only spatial light modulator, which can suppress the side lobe and smooth energy oscillations effectively. The LDFB is used for rapid fabrication of HAR micropillars and various microstructures, which greatly increases the fabrication efficiency. As a demonstration, several typical HAR microstructures such as assemblies, microchannels, microtubes, and cell scaffolds are prepared. Moreover, the microcapture arrays are rapidly fabricated for the capture of microspheres and the formation of microlens arrays, which show focusing and imaging ability.

4.
Chem Commun (Camb) ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32364191

RESUMO

Quantum dots with narrow emission line width have persistently received attention for their applications in biological imaging, lasers and next-generation displays. We herein report a cation exchange assisted shelling approach changing the starting CdSe emitting cores into new ZnCdSe alloy emitting cores and finally ZnCdSe/ZnSe core/shell QDs. The resulting ZnCdSe/ZnSe QDs exhibit an emission line width as narrow as 17.1 nm with a near-unity photoluminescence quantum yield and a single emission channel. We anticipate that our study on a cation exchange assisted synthetic route for controlling the emission line widths of the QDs could be extended to high-quality green and blue ones beyond currently achieved.

5.
Mol Cancer Ther ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404407

RESUMO

Focal adhesion kinase (FAK) promotes cancer cell growth and metastasis. We previously reported that FAK inhibition by the selective inhibitor VS-4718 exerted anti-leukemia activities in AML. The mechanisms involved, and whether VS-4718 potentiates efficacy of other therapeutic agents, have not been investigated. Resistance to apoptosis inducted by the BCL-2 inhibitor ABT-199 (venetoclax) in AML is mediated by pre-existing and ABT-199-induced overexpression of MCL-1 and BCL-XL. We observed that VS-4718 or silencing FAK with siRNA decreased MCL-1 and BCL-XL levels. Importantly, VS-4718 antagonized ABT-199-induced MCL-1 and BCL-XL. VS-4718 markedly synergized with ABT-199 to induce apoptosis in AML cells, including primary AML CD34+ cells and AML cells overexpressing MCL-1 or BCL-XL. In a PDX model derived from a patient sample with NPM1/FLT3-ITD/TET2/DNMT3A/WT1 mutations and complex karyotype, VS-4718 statistically significantly reduced leukemia tissue infiltration and extended survival (72 vs control 36 d, p = 0.0002), and only its combination with ABT-199 effectively decreased systemic leukemia tissue infiltration and circulating blasts, and prolonged survival (65.5 vs control 36 d, p = 0.0119). Furthermore, the combination decreased NF-κB signaling and induced the expression of interferon genes in vivo. The combination also markedly extended survival of a second PDX model developed from an aggressive, p53-mutated complex karyotype AML sample. The data suggest that the combined inhibition of FAK and BCL-2 enhances anti-leukemia activity in AML at least in part by suppressing MCL-1 and BCL-XL and that this combination may be effective in AML with p53 and other mutations, and thus benefit high-risk AML patients.

6.
Virol Sin ; 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385724

RESUMO

The spread of H5 highly pathogenic avian influenza viruses poses serious threats to the poultry industry, wild bird ecology and human health. Circulation of H5 viruses between poultry and wild birds is a significant public health threat in China. Thus, viral migration networks in this region need to be urgently studied. Here, we conducted molecular genetic analyses of the hemagglutinin genes of H5 highly pathogenic avian influenza viruses in multiple hosts from 2000 to 2018 in China. Our aim was to clarify the roles of different hosts in the evolution of H5 viruses. We used a flexible Bayesian statistical framework to simulate viral space diffusion and continuous-time Markov chains to infer the dynamic evolutionary process of spatiotemporal dissemination. Bayesian phylogeographic analysis of H5 viruses showed for the first time that H5 viruses in poultry and wild birds were present in Guangdong Province. Furthermore, Guangdong, Jiangsu, Shanghai and Hunan acted as the epicenters for the spread of various H5 subtypes viruses in poultry, and Henan, Shanghai, Hong Kong and Inner Mongolia acted as epicenters for the spread of various H5 subtypes viruses in wild birds. Thus, H5 viruses exhibited distinct evolutionary dynamics in poultry and wild birds. Our findings extend our understanding of the transmission and spread of highly pathogenic H5 avian influenza viruses in China.

7.
ACS Nano ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32383849

RESUMO

Emerging evidence indicates that mitochondria contribute to drug resistance in cancer, but how to selectively target the mitochondria of cancer cells remains less explored. Here, we show perimitochondrial enzymatic self-assembly for selectively targeting the mitochondria of liver cancer cells. Nanoparticles of a peptide-lipid conjugate, being a substrate of enterokinase (ENTK), encapsulate chloramphenicol (CLRP), a clinically used antibiotic that is deactivated by glucuronidases in cytosol but not in mitochondria. Perimitochondrial ENTK cleaves the Flag-tag on the conjugate to deliver CLRP selectively into the mitochondria of cancer cells, thus inhibiting the mitochondrial protein synthesis, inducing the release of cytochrome c into the cytosol and resulting in cancer cell death. This strategy selectively targets liver cancer cells over normal liver cells. Moreover, blocking the mitochondrial protein synthesis sensitizes the cancer cells, relying on glycolysis and/or OXPHOS, to cisplatin. This work illustrates a facile approach, selectively targeting mitochondria of cancer cells and repurposing clinically approved ribosome inhibitors, to interrupt the metabolism of cancer cells for cancer treatment.

8.
Medicine (Baltimore) ; 99(15): e19806, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282746

RESUMO

RATIONALE: Acute lymphoblastic leukemia (ALL) has acute and severe onset characterized by fever, moderate to severe anemia, bone and joint pain, and sternal tenderness. It is easy to be misdiagnosed as rheumatic disease when joint pain is the first symptom. PATIENT CONCERNS: A male Han, 18 years of age was admitted on July 15th, 2016 for multi-joint swelling and pain with intermittent fever for half a year which had aggravated in the last 10 days. DIAGNOSIS: Based on symptoms, imaging, family history, and blood tests, he was first diagnosed with ankylosing spondylitis, but he was refractory to treatment. Bone marrow biopsy then revealed acute B-lymphoblastic leukemia (possibility Pro-B-ALL). INTERVENTIONS: The patient was transferred to the hematology department on July 23rd, 2016 for chemotherapy. OUTCOMES: No joint pain occurred during follow-up, which ended on November 4th, 2018. LESSONS: ALL may present with symptoms suggestive of rheumatic diseases like ankylosing spondylitis. Physicians should be aware of this possibility, especially in young patients.


Assuntos
Artralgia/etiologia , Leucemia Linfocítica Crônica de Células B/patologia , Espondilite Anquilosante/diagnóstico , Adolescente , Antineoplásicos/uso terapêutico , Artralgia/diagnóstico , Biópsia , Medula Óssea/patologia , Diagnóstico Diferencial , Erros de Diagnóstico , Febre/diagnóstico , Febre/etiologia , Humanos , Artropatias/diagnóstico por imagem , Artropatias/patologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Espondilite Anquilosante/sangue , Espondilite Anquilosante/terapia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
9.
Zhongguo Zhong Yao Za Zhi ; 45(2): 221-232, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237303

RESUMO

Along with the striding of the Chinese medicine(CM) manufacturing toward the Industry 4.0, some digital factories have accumulated lightweight industrial big data, which become part of the enterprise assets. These digital assets possess the possibility of solving the problems within the CM production system, like the Sigma gap and the poverty of manufacturing knowledge. From the holistic perspective, a three-tiered architecture of CM industrial big data is put forward, and it consists of the data integration layer, the data analysis layer and the application scenarios layer. In data integration layer, sensing of CM critical quality attributes is the key technology for big data collection. In data analysis and mining layer, the self-developed iTCM algorithm library and model library are introduced to facilitate the implementation of the model lifecycle methodologies, including process model development, model validation, model configuration and model maintenance. The CM quality transfer structure is closely related with the connection mode of multiple production units. The system modeling technologies, such as the partition-integration modeling method, the expanding modeling method and path modeling method, are key to mapping the structure of real manufacturing system. It is pointed out that advance modeling approaches that combine the first-principles driven and data driven technologies are promising in the future. At last, real-world applications of CM industrial big data in manufacturing of injections, oral solid dosages, and formula particles are presented. It is shown that the industrial big data can help process diagnosis, quality forming mechanism interpretations, real time release testing method development and intelligent product formulation design. As renewable resources, the CM industrial big data enable the manufacturing knowledge accumulation and product quality improvement, laying the foundation of intelligent manufacturing.

10.
Zhongguo Zhong Yao Za Zhi ; 45(2): 233-241, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237304

RESUMO

Lonicerae Japonicae Flos and Artemisiae Annuae Herba(LA or Jinqing) alcohol precipitation has various process parameters and complex process mechanism, and is one of the key units for manufacturing Reduning Injection. In order to identify the critical process parameters(CPPs) affecting the weight of the extract produced from the alcohol precipitation process, 259 batches of historical production data from 2017 to 2018 were collected, with a total of 829 318 data points. These data showed characteristics of large data, such as a large data volume, a low value density, and diverse sources. The data cleaning and feature extraction were first performed, and 48 feature variables were selected. The original data points were reduced to 9 936. Then, a combination of Pearson correlation analysis and grey correlation analysis were used to screen out 15 potential critical process parameters(pCPPs). After that, the partial least squares(PLS) was used in prediction of the weight of the extract, proving that the performance of predictive model based on 15 pCMAs is equivalent to that of predictive model based on 48 feature variables. The variable importance in projection(VIP) index was used to identify 9 CPPs, including 2 alcohol precipitation supernatant volume parameters, 4 initial extract weight parameters and 3 added alcohol volume parameters. As a result, the number of data points was 1 863, accounting for 0.28% of the original data. The big data analysis approach from a holistic point of view can effectively increase the value density of the original data. The critical process parameters obtained can help to accurately describe the quality transfer mechanism of the Jinqing alcohol precipitation process.

11.
Zhongguo Zhong Yao Za Zhi ; 45(2): 242-249, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237305

RESUMO

To control the risks of powder caking and capsule shell embrittlement of Guizhi Fuling Capsules, a predictive model for hygroscopicity of contents in Guizhi Fuling Capsules was built. A total of 90 batches of samples, including raw materials, intermediate powders and capsules, were collected during the manufacturing of Guizhi Fuling Capsules. According to the production sequence, 47 batches were used as the calibration set, and the properties of raw materials and the four intermediate powders were comprehensively characterized by the physical fingerprint. Then, the partial least squares(PLS) model was developed with the content hygroscopicity as the response variable. The variable importance in projection(VIP), variance inflation factor(VIF) and regression coefficients were used to screen out potential critical material attributes(pCMAs). As a result, five pCMAs from 54 physical parameters were screened out. Furthermore, different models were built by different combinations of pCMAs, and their predictive robustness of 43 batches was evaluated on the basis of the validation set. Finally, the tap density(D_c) of wet granules obtained from wet granulation and the angle of repose(α) of raw materials were identified as the critical material attributes(CMAs) affecting the hygroscopicity of the contents of Guizhi Fuling Capsules. The prediction model established with the two CMAs as independent variables had an average relative prediction error of 2.68% for samples in the validation set, indicating a good accuracy of prediction. This paper proved the feasibility of predictive modeling toward the control of critical quality attributes of Chinese medicine oral solid dosage(OSD). The combination of the continuous quality improvement, the industrial big data and the process modeling technique paved the way for the intelligent manufacturing of Chinese medicine oral solid preparations.

12.
Zhongguo Zhong Yao Za Zhi ; 45(2): 250-258, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237306

RESUMO

In this paper, a real time release testing(RTRT) model for predicting the disintegration time of Tianshu tablets was established on the basis of the concept of quality by design(QbD), in order to improve the quality controllability of the production process. First, 49 batches of raw materials and intermediates were collected. Afterwards, the physical quality attributes of all materials were comprehensively characterized. The partial least square(PLS) regression model was established with the 72 physical quality attributes of raw materials and intermediates as input and the disintegration time(DT) of uncoated tablets as output. Then, the variable screening was carried out based on the variable importance in the projection(VIP) indexes. Moisture content of raw materials(%HR), tapped density of wet masses(D_c), hygroscopicity of dry granules(%H), moisture content of milling granules(%HR) and Carr's index of mixed granules(IC) were determined as the potential critical material attributes(pCMAs). According to the effects of interactions of pCMAs on the performance of the prediction model, it was finally determined that the wet masses' D_c and the dry granules'%H were critical material attributes(CMAs). A RTRT model of the disintegration time prediction was established as DT=34.09+2×D_c+3.59×%H-5.29×%H×D_c,with R~2 equaling to 0.901 7 and the adjusted R~2 equaling to 0.893 3. The average relative prediction error of validation set for the RTRT model was 3.69%. The control limits of the CMAs were determined as 0.55 g·cm~(-3)<D_c<0.63 g·cm~(-3) and 4.77<%H<7.59 according to the design space. The RTRT model of the disintegration time reflects the understanding of the process system, and lays a foundation for the implementation of intelligent control strategy of the key process of Tianshu Tablets.

13.
Zhongguo Zhong Yao Za Zhi ; 45(2): 259-266, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237307

RESUMO

In this paper, the inline turbidity sensor technology was used to quantify the turbidity of the solution during the dissolution of Chinese medicine granules. The probe measurement position and the magnetic stirring speed were optimized. As a result, the stirring speed was 400 r·min~(-1), and the probe position was at 1/4 of the diameter of the beaker. The measurement results were accurate and reliable. Totally 105 batches of commercially available Chinese medicine granules were collected and dissolved according to the requirements of the Chinese Pharmacopoeia. At the time point of 5 min, 57 batches of granules were completely dissolved, and the corresponding turbidity values ranged between 0-70 FTU; 32 batches of granules showed a slight turbidity, and the corresponding turbidity values ranged between 70-350 FTU; 14 batches of granule solution were turbid, and the corresponding turbidity values ranged between 350-2 000 FTU; two batches of granule solution were heavily turbid, and the corresponding turbidity values were >2 000 FTU. Among the above results, the number of batches in line with the pharmacopoeia dissolution requirement was 84.76%, and the dissolution of some granules still needed to be improved. The turbidity sensor recorded the change curve of turbidity value over time(solubility behavior curve). The degree of important of disintegration and dissolution during the dissolution process showed disintegration > dissolution, disintegration≈dissolution, disintegration < dissolution. The dissolution behavior of the granules can be classified into three categories. The analysis of the mechanism in the process of granule solubility provides a basis for product process improvement.

14.
Zhongguo Zhong Yao Za Zhi ; 45(2): 267-273, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237308

RESUMO

In this study, the texture analyzer acupuncture pressure sensor was used to objectively characterize the "herb soaking with exact amount of water" for moistening process of ginseng. The single factor rotation experiment was used to investigate the effects of puncture speed, puncture depth and puncture site on puncture force and work. According to ginseng processing method in Chinese Pharmacopoeia, ginseng medicinal materials with diameters of about 1 cm and 2 cm were selected, and puncture experiments were carried out at the set measurement time to determine the hardness, work and water absorption of the ginseng moistening process. The endpoint threshold for the ginseng softening process was determined and verified. To reflect the actual internal conditions of the ginseng softening process, the puncture depth was preferably 70%, and the puncture speed was 30 mm·min~(-1). In the ginseng moistening process, the softening hardness and the puncture work were in accordance with the first-order kinetic equation y=a×exp(-k×x). The 0 h initial hardness a of 1 cm and 2 cm ginseng herbs were 289.8 N and 1 227 N, and the rate constants K were 0.149 4 N·h~(-1) and 0.100 7 N·h~(-1), respectively. After the ginseng was completely softened, the force required for puncture was 10 N, which can be used as the standard for "drug penetration". At this time, the water absorption rate of ginseng was 70%-100%. The softening time of ginseng with a diameter of 1 cm was about 20-22 h, and the softening time of ginseng with a diameter of 2 cm was about 40-46 h. A needle-type pressure sensor was used to accurately determine the end point of the softening process of ginseng and reduce the loss of active ingredients. The study results provide reference for the softening process kinetics and the process intelligent monitoring of other dried roots and rhizomes.

15.
Zhongguo Zhong Yao Za Zhi ; 45(2): 274-284, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237309

RESUMO

In this paper, five representative Chinese herbal decoction pieces of Scutellariae Radix, Paeoniae Radix Alba, vinegar-processed Corydalis Rhizoma, Polygoni Multiflori Radix Praeparata and Lonicerae Japonicae Flos were selected to prepare the corresponding fine powder of pieces, extract powder, semi-extract powder and physical mixed powder. The physical properties of 20 kinds of powders, such as related parameters of particle size, density, stability and flowability, were evaluated comprehensively. The compression curves of powder porosity and tensile strength changing with pressure were plotted, and the Heckel equation and the Kawakita equation were used to describe the powder compression behavior. The results showed that compared with the fine powder of pieces, the compressibility of the semi-extract powder and the extract powder was significantly improved. Compared with the extract powder, the particle size and relative uniformity of the semi-extract powder were increased, indicating that the uniformity of the powder was improved. Besides, the semi-extract powder could reduce the hygroscopicity of the powder. Particularly, the semi-extract powder of Scutellariae Radix, Paeoniae Radix Alba and vinegar-processed Corydalis Rhizoma could maintain the porous structure of the tablet even under a high tableting pressure, which was beneficial to tablet disintegration. For some traditional Chinese medicines(such as Lonicerae Japonicae Flos), the semi-extract powder could reduce the viscosity, which avoided the sticking in the die compression. The semi-extract powder and the physical mixture powder prepared by the same Chinese herbal decoction pieces had similar physical properties and compression behaviors. Principal component analysis(PCA) was carried out on the 17 physical attributes and 5 compression parameters of the powder. It was found that the first principal component mainly reflected the differences among the material sources, while the second principal component could reflect the differences among fine powder of pieces, extract powder, semi-extract powder and physical mixed powder originating from the same Chinese herbal decoction pieces. In this paper, the mechanism of "unification of drugs and excipients" of Chinese medicine semi-extract powder was explained in terms of physical properties and compression behavior of powders, which provided reference for the formulation design and process development of Chinese medicine tablets.

16.
Mol Immunol ; 122: 69-79, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32305690

RESUMO

Recent studies have shown that aberrant activation of the complement system plays an important role in the pathogenesis of preeclampsia. There is evidence to suggest that aberrant activation of the complement system may already be present during the first trimester. Here, we performed a prospective study in which peripheral blood samples were collected from 500 women during pregnancy. Twenty-one patients (41 specimens) suffering from preeclampsia later in pregnancy were classified into the study group, and sixty-three gravidas with normal pregnancies (136 specimens) were selected as the control group. The plasma concentrations of complement factor B (CFB), C1q, complement factor H (CFH), C3c, C4, C3a, C5a and soluble C5b-9 (sC5b-9) were measured. The levels of CFB (P = 0.004), CFH (P = 0.002), C1q (P = 0.044), C3c (P = 0.032) and C4 (P = 0.015) were significantly higher in preeclampsia than in normal pregnancy during the first trimester, and these levels became similar to those in normal pregnancy thereafter. Before the onset of preeclampsia, the levels of C3a, C5a and sC5b-9 in the preeclampsia group were similar to those in control group even in late pregnancy. C3a levels showed a significant positive correlation with C5a in normal pregnancy (r=0.658, P<0.01) but not in preeclampsia (r = 0.001, P = 1).Thus, we found that aberrant activation of the complement system in patients with preeclampsia was initiated during the first trimester but returned to normal pregnancy levels in the second trimester. At the same time, there is aberrant regulation of complement activation at the C3a-C5a level in preeclampsia during pregnancy.

17.
J Am Chem Soc ; 142(17): 7858-7867, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32259437

RESUMO

Optical voltage sensors with the ability to monitor neuronal activities are invaluable tools for studying information processing of the brain. However, the current genetically encoded voltage indicators usually require high-power visible light for excitation and are limited to genetically addressable model animals. Here, we report a near-infrared (NIR)-excited nongenetic voltage nanosensor that achieves stable recording of neuronal membrane potential in intact animals. The nanosensor is composed of a Förster resonance energy transfer (FRET) pair, the outer membrane-anchored upconversion nanoparticle (UCNP), and the membrane-embedded dipicrylamine (DPA). The negative charge of DPA allows membrane potential fluctuation to affect the distance between the DPA and UCNP, therefore changing the FRET efficiency. Consequently, the emission intensity of the nanosensor can report the membrane potential. Using the nanosensor, we monitor not only electrically evoked changes in the membrane potential of cultured cells but also sensory responses of neurons in intact zebrafish and brain state-modulated subthreshold activities of cortical neurons in intact mice.

18.
Sci Rep ; 10(1): 6904, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327682

RESUMO

In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1-4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.

19.
Environ Int ; 139: 105558, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32278201

RESUMO

Air pollution over China has attracted wide interest from public and academic community. PM2.5 is the primary air pollutant across China. Quantifying interactions between meteorological conditions and PM2.5 concentrations are essential to understand the variability of PM2.5 and seek methods to control PM2.5. Since 2013, the measurement of PM2.5 has been widely made at 1436 stations across the country and more than 300 papers focusing on PM2.5-meteorology interactions have been published. This article is a comprehensive review on the meteorological impact on PM2.5 concentrations. We start with an introduction of general meteorological conditions and PM2.5 concentrations across China, and then seasonal and spatial variations of meteorological influences on PM2.5 concentrations. Next, major methods used to quantify meteorological influences on PM2.5 concentrations are checked and compared. We find that causality analysis methods are more suitable for extracting the influence of individual meteorological factors whilst statistical models are good at quantifying the overall effect of multiple meteorological factors on PM2.5 concentrations. Chemical Transport Models (CTMs) have the potential to provide dynamic estimation of PM2.5 concentrations by considering anthropogenic emissions and the transport and evolution of pollutants. We then comprehensively examine the mechanisms how major meteorological factors may impact the PM2.5 concentrations, including the dispersion, growth, chemical production, photolysis, and deposition of PM2.5. The feedback effects of PM2.5 concentrations on meteorological factors are also carefully examined. Based on this review, suggestions on future research and major meteorological approaches for mitigating PM2.5 pollution are made finally.

20.
Pharmacol Res Perspect ; 8(2): e00593, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32338459

RESUMO

To assess bioequivalence of a generic dabigatran etexilate capsule in healthy Chinese subjects under fasting and fed conditions. This was an open-label, single-center, randomized four-period crossover study with a 7-day washout period. A single oral dose of 150 mg generic dabigatran etexilate capsule (test drug) or a commercial dabigatran etexilate capsule (Pradaxa® , reference drug) was given to healthy volunteers under the fasting and fed conditions. Plasma concentrations of total and free dabigatran were detected using a validated HPLC-MS/MS method. A noncompartmental method was used for pharmacokinetic analysis and established coagulation assays were applied for pharmacodynamic analysis. The 90% CIs of the test/reference ratios of Cmax , AUC0-t , and AUC0-∞ for the total dabigatran concentration were 92.57%-106.58%, 91.63%-106.32%, and 92.54%-106.17%, respectively, under fasting condition, and 99.30%-110.74%, 98.58%-105.37%, and 97.75%-103.99%, respectively, under fed conditions. The 90% CIs of the ratios of the parameters for the free dabigatran were 93.18%-106.98%, 92.13%-107.10%, 92.89%-106.48%, respectively, under fasting condition, and 100.05%-110.89%, 99.37%-106.23%, 97.59%-103.98%, respectively, under the fed condition. Additionally, the upper limit of the 90% CIs for σWT/σWR was below 2.5. There were no significant differences in the coagulation parameters including thrombin clotting time, activated partial thromboplastin time, and anti-IIa activity between the two preparations. The generic dabigatran etexilate capsule is bioequivalent to the brand-named product in healthy Chinese volunteers under fasting and fed conditions. The two products have comparable pharmacodynamic parameters, with a good safety profile. In addition, food intake influences absorption of both products in a similar way.

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