Phenyl Derivatives Modulate the Luminescent Properties and Stability of CzBTM-Type Radicals.

The distinctive electron structures of luminescent radicals offer considerable potential for a diverse array of applications. Up to now, the luminescent properties of radicals have been modulated through the introduction of electron-donating substituents, predominantly derivatives of carbazole and polyaromatic amines with more and more complicated structures and redshifted luminescent spectra. Herein, four kinds of (N-carbazolyl)bis(2,4,6-tirchlorophenyl)-methyl (CzBTM) radicals, Ph2CzBTM, Mes2CzBTM, Ph2PyIDBTM, and Mes2PyIDBTM, were synthesized and characterized by introducing simple phenyl and 2,4,6-trimethylphenyl groups to CzBTM and PyIDBTM. These radicals exhibit rare blueshifted emission spectra compared to their parent radicals. Furthermore, modifications to CzBTM significantly enhanced the photoluminescence quantum yields (PLQYs), with a highest PLQY of 21% for Mes2CzBTM among CzBTM-type radicals. Additionally, the molecular structures, photophysical properties of molecular orbitals, and stability of the four radicals were systematically investigated. This study provides a novel strategy for tuning the luminescent color of radicals to shorter wavelengths and improving thermostability.

The Successive Next Network as Augmented Regularization for Deformable Brain MR Image Registration.

Deep-learning-based registration methods can not only save time but also automatically extract deep features from images. In order to obtain better registration performance, many scholars use cascade networks to realize a coarse-to-fine registration progress. However, such cascade networks will increase network parameters by an n-times multiplication factor and entail long training and testing stages. In this paper, we only use a cascade network in the training stage. Unlike others, the role of the second network is to improve the registration performance of the first network and function as an augmented regularization term in the whole process. In the training stage, the mean squared error loss function between the dense deformation field (DDF) with which the second network has been trained and the zero field is added to constrain the learned DDF such that it tends to 0 at each position and to compel the first network to conceive of a better deformation field and improve the network's registration performance. In the testing stage, only the first network is used to estimate a better DDF; the second network is not used again. The advantages of this kind of design are reflected in two aspects: (1) it retains the good registration performance of the cascade network; (2) it retains the time efficiency of the single network in the testing stage. The experimental results show that the proposed method effectively improves the network's registration performance compared to other state-of-the-art methods.

Improving the Luminescence and Stability of Carbon-Centered Radicals by Kinetic Isotope Effect.

The kinetic isotope effect (KIE) is beneficial to improve the performance of luminescent molecules and relevant light-emitting diodes. In this work, the influences of deuteration on the photophysical property and stability of luminescent radicals are investigated for the first time. Four deuterated radicals based on biphenylmethyl, triphenylmethyl, and deuterated carbazole were synthesized and sufficiently characterized. The deuterated radicals exhibited excellent redox stability, as well as improved thermal and photostability. The appropriate deuteration of relevant C-H bonds would effectively suppress the non-radiative process, resulting in the increase in photoluminescence quantum efficiency (PLQE). This research has demonstrated that the introduction of deuterium atoms could be an effective pathway to develop high-performance luminescent radicals.

Influence of Fine Ligand Substitution Modification of the Isocyanidometal Bridge on Metal-to-Metal Charge Transfer Properties in Class II-III Mixed Valence Complexes.

The synthesis and characterization of Class II-III mixed valence complexes have been an interesting topic due to their special intermediate behaviour between localized and delocalized mixed valence complexes. To investigate the influence of the isocyanidometal bridge on metal-to-metal charge transfer (MMCT) properties, a family of new isocyanidometal-bridged complexes and their one-electron oxidation products cis-[Cp(dppe)Fe-CN-Ru(L)2 -NC-Fe(dppe)Cp][PF6 ]n (n=2, 3) (Cp=1,3-cyclopentadiene, dppe=1,2-bis(diphenylphosphino)ethane, L=2,2'-bipyridine (bpy, 1[PF6 ]n ), 5,5'-dimethyl-2,2'-bipyridyl (5,5'-dmbpy, 2[PF6 ]n ) and 4,4'-dimethyl-2,2'-bipyridyl (4,4'-dmbpy, 3[PF6 ]n )) have been synthesized and fully characterized. The experimental results suggest that all the one-electron oxidation products may belong to Class II-III mixed valence complexes, supported by TDDFT calculations. With the change of the substituents of the bipyridyl ligand on the Ru centre from H, 5,5'-dimethyl to 4,4'-dimethyl, the energy of MMCT for the one-electron oxidation complexes changes in the order: 13+ <23+ <33+ , and that for the two-electron oxidation complexes decreases in the order 14+ >34+ >24+ . The potential splitting (ΔE1/2 (2)) between the two terminal Fe centres for N[PF6 ]2 are the largest potential splitting for the cyanido-bridged complexes reported so far. This work shows that the smaller potential difference between the bridging and the terminal metal centres would result in the more delocalized mixed valence complex.

CircRNA hsa_circ_0030018 regulates the development of glioma via regulating the miR-1297/RAB21 axis.

Circular RNAs (circRNAs) play a crucial role in tumor occurrence and progression. And the dysregulated circRNAs are reported to be relevant to glioma development. Nevertheless, the function and regulatory mechanism of hsa_circ_0030018 in glioma progression are largely indistinct. The abundances of hsa_circ_0030018, miR-1297, and RAB21 were detected using quantitative real-time polymerase chain reaction or western blot. Cell proliferation was assessed via colony formation assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell apoptosis and cell cycle progression were evaluated by flow cytometry. Cell migration and invasion were examined using transwell assay and wound healing assay. The protein levels were measured by western blot. The interaction between miR-1297 and hsa_circ_0030018 or RAB21 was validated via dual-luciferase reporter analysis, RNA immunoprecipitation (RIP), and RNA pull-down assays. A xenograft model experiment was performed to analyze the function of hsa_circ_0030018 on tumor growth in vivo. hsa_circ_0030018 and RAB21 levels were enhanced, and the miR-1297 level was reduced in glioma tissues and cells. The silence of hsa_circ_0030018 or overexpression of miR-1297 impeded cell proliferation, metastasis, and expedited cell apoptosis and cycle arrest in glioma cells. Furthermore, hsa_circ_0030018 modulated glioma malignant behaviors via sponging miR-1297, and miR-1297 suppressed glioma development via targeting RAB21. Moreover, hsa_circ_0030018 knockdown inhibited tumor growth in vivo. The hsa_circ_0030018 knockdown repressed glioma progression by mediating the miR-1297/RAB21 pathway, providing potential therapeutic targets for glioma treatment.

The Role of Metal-Organic Frameworks in Electronic Sensors.

MOFs have a highly ordered self-assembled nanostructure, high surface area, nanoporosity with tunable size and shape, reliable host-guest interactions, and responsiveness to physical and chemical stimuli which can be exploited to address critical issues in sensor applications. On the one hand, the nanoscale pore size of MOFs ranging from less than 1 nm to ≈ 10 nm not only allows the diffusion of small molecules into the pores or through the MOF layer, but also excludes other larger molecules depending on the size, shape, and conformation of MOFs. On the other hand, MOFs with flexible structure exhibit a dynamic response to external stimuli, including guest molecules, temperature, pressure, pH, and light. Due to the unsaturated coordination metal sites and active functional groups, the interaction between certain analytes and active sites results in high selectivity. In this review, we summarize the latest studies on MOF-based electronic sensors in terms of the function of MOFs, discuss challenges, and suggest perspectives.

Chromaticity-based real-time assessment of melanopic and luminous efficiency of smartphone displays.

We investigate the spectral power distributions of 54 phones (33 measured experimentally in default text mode and 21 downloaded from the web) and estimate the mean ± std. dev. of the luminous efficiency of radiation, melanopic efficiency of radiation, and melanopic/photopic ratio as 287 ± 13 lm/W, 303 ± 26 blm/W, and 1.06 ± 0.13, respectively. We establish the chromaticity-performance characteristics relation to precisely assess the action efficiency of radiation performance using either RGB gray values or CIE xy values. Our real-time assessment of smartphone displays can aid in reducing energy consumption and improving user health.

A Diruthenium-Based Mixed Spin Complex Ru2 5+ (S=1/2)-CN-Ru2 5+ (S=3/2).

An unusual tetra-nuclear linear cyanido-bridged complex [Ru2 (µ-ap)4 -CN-Ru2 (µ-ap)4 ](BPh4 ) (1) (ap=2-anilinopyridinate) has been synthesized and well characterized. The crystallographic data, magnetic measurement, IR, EPR and theoretical calculation results demonstrate that complex 1 is the first example of mixed spin Ru2 5+ -based complex with uncommon electronic configurations of S=1/2 for the cyanido-C bound Ru2 5+ and S=3/2 for the cyanido-N bound Ru2 5+ . This phenomenon can be understood by the theoretical calculation results that from the precursor Ru2 (µ-ap)4 (CN) (S=3/2) to complex 1 the energy gap between π* and δ* orbitals of the cyanido-C bound Ru2 5+ core increases from 0.57 to 1.61 eV due to the enhancement of asymmetrical π back-bonding effect, but that of the cyanido-N bound Ru2 5+ core is essential identical (0.56 eV). Besides, the analysis of UV/Vis-NIR spectra suggests that there exists metal to metal charge transfer (MMCT) from the cyanido-N bound Ru2 5+ (S=3/2) to the cyanido-C bound Ru2 5+ (S=1/2), supported by the TDDFT calculations.

Different Degrees of Electron Delocalization in Mixed Valence Ru-Ru-Ru Compounds by Cyanido-/Isocyanido-Bridge Isomerism.

The two stable pairs of trimetallic compounds trans-[Cp*(dppe)Ru(µ-NC)Ru(dmap)4 (µ-CN)Ru(dppe)Cp*][PF6 ]n (1[PF6 ]n , n=2, 3; Cp*=1,2,3,4,5-pentamethylcyclopentadiene; dppe=1,2-bis-(diphenylphosphino)ethane; dmap= 4-dimethylaminopyridine) and trans-[Cp*(dppe)Ru(µ-CN)Ru(dmap)4 (µ-NC)Ru(dppe)Cp*][PF6 ]n (2[PF6 ]n , n=2, 3), which demonstrate cyanide/isocyanide isomerism, have been synthesized and fully characterized. 13+ [PF6 ]3 and 23+ [PF6 ]3 are the one-electron oxidation products of 12+ [PF6 ]2 and 22+ [PF6 ]2 , respectively. The results suggest that 1[PF6 ]3 is a class III mixed valence compound, whereas 2[PF6 ]3 might be an unusually symmetrical class II-III mixed valence compound composed of the two asymmetrical delocalized RuIII -NC-RuII mixed valence subunits.

Translocation of microbes and changes of immunocytes in the gut of rapid- and slow-progressor Chinese rhesus macaques infected with SIVmac239.

Human/simian immunodeficiency virus (HIV/SIV) infection can cause severe depletion of CD4(+) T cells in both plasma and mucosa; it also results in damage to the gut mucosa barrier, which makes the condition more conducive to microbial translocation. In this study, we used SIV-infected Chinese rhesus macaques to quantify the extent of microbial translocation and the function of immune cells in the entire gastrointestinal tract and to compare their differences between rapid and slow progressors. The results showed that in the slow progressors, microbial products translocated considerably and deeply into the lamina propria of the gut; the tissue macrophages had no significant differences compared with the rapid progressors, but there was a slightly higher percentage of mucosal CD8(+) T cells and a large amount of extracellular microbial products in the lamina propria of the intestinal mucosa of the slow progressors. The data suggested that although microbial translocation increased markedly, the mucosal macrophages and CD8(+) T cells were insufficient to clear the infiltrated microbes in the slow progressors. Also, therapies aimed at suppressing the translocation of microbial products in the mucosa could help to delay the progression of SIV disease.

High immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected Chinese rhesus macaques.

Chinese rhesus macaques (CRMs) are ideal experimental animals for studying the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and for vaccine research. SHIV89.6 has been reported to be an attenuated virus because, in most cases, SHIV89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. After two serial passages in vivo, SHIV (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. However, the pathogenic ability of SHIV89.6 is not well understood. In this study, we found that 6 of 14 SHIV89.6-infected CRMs died within 127 weeks after infection. We found especially high immune activation, low IFN-α expression, and distinctive cytokine expression profiles in the infected and dead (ID) group of monkeys, while there was only few change in the CD4(+) T counts and distribution of T cell subsets in the ID group monkeys. Also, there was a similar dynamic of viral load between infected and surviving (IS) and ID group monkeys. Furthermore, we found various correlations among immune activation, IFN-α expression, and frequencies of cytokine-secreting cells. These results suggest that SHIV89.6 infections have pathogenic potential in CRMs and that high immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected CRMs. This also implies that high immune activation may be relevant to dysfunction of immune cells. It is proposed that high immune activation and dysfunction of immune cells may be good predictors for disease progression and markers for therapy.

Hybrid representation learning for cognitive diagnosis in late-life depression over 5 years with structural MRI.

Late-life depression (LLD) is a highly prevalent mood disorder occurring in older adults and is frequently accompanied by cognitive impairment (CI). Studies have shown that LLD may increase the risk of Alzheimer's disease (AD). However, the heterogeneity of presentation of geriatric depression suggests that multiple biological mechanisms may underlie it. Current biological research on LLD progression incorporates machine learning that combines neuroimaging data with clinical observations. There are few studies on incident cognitive diagnostic outcomes in LLD based on structural MRI (sMRI). In this paper, we describe the development of a hybrid representation learning (HRL) framework for predicting cognitive diagnosis over 5 years based on T1-weighted sMRI data. Specifically, we first extract prediction-oriented MRI features via a deep neural network, and then integrate them with handcrafted MRI features via a Transformer encoder for cognitive diagnosis prediction. Two tasks are investigated in this work, including (1) identifying cognitively normal subjects with LLD and never-depressed older healthy subjects, and (2) identifying LLD subjects who developed CI (or even AD) and those who stayed cognitively normal over five years. We validate the proposed HRL on 294 subjects with T1-weighted MRIs from two clinically harmonized studies. Experimental results suggest that the HRL outperforms several classical machine learning and state-of-the-art deep learning methods in LLD identification and prediction tasks.

Epidemiologic changes of a longitudinal surveillance study spanning 51 years of scrub typhus in mainland China.

Scrub typhus may be one of the world's most prevalent, neglected and serious, but easily treatable, febrile diseases. It has become a significant potential threat to public health in China. In this study we used national disease surveillance data to analyze the incidence and spatial-temporal distribution of scrub typhus in mainland China during 1952-1989 and 2006-2018. Descriptive epidemiological methods and spatial-temporal epidemiological methods were used to investigate the epidemiological trends and identify high-risk regions of scrub typhus infection. Over the 51-year period, a total of 182,991 cases and 186 deaths were notified. The average annual incidence was 0.13 cases/100,000 population during 1952-1989. The incidence increased sharply from 0.09/100,000 population in 2006 to 1.93/100,000 population in 2018 and then exponentially increased after 2006. The incidence was significantly higher in females than males (χ2 = 426.32, P < 0.001). Farmers had a higher incidence of scrub typhus than non-farmers (χ2 = 684.58, P < 0.001). The majority of cases each year were reported between July and November with peak incidence occurring during October each year. The trend surface analysis showed that the incidence of scrub typhus increased gradually from north to south, and from east and west to the central area. The spatial autocorrelation analysis showed that a spatial positive correlation existed in the prevalence of scrub typhus on a national scale, which had the characteristic of aggregated distribution (I = 0.533, P < 0.05). LISA analysis showed hotspots (High-High) were primarily located in the southern and southwestern provinces of China with the geographical area expanding annually. These findings provide scientific evidence for the surveillance and control of scrub typhus which may contribute to targeted strategies and measures for the government.

Deep learning based brain MRI registration driven by local-signed-distance fields of segmentation maps.

BACKGROUND: Deep learning based unsupervised registration utilizes the intensity information to align images. To avoid the influence of intensity variation and improve the registration accuracy, unsupervised and weakly-supervised registration are combined, namely, dually-supervised registration. However, the estimated dense deformation fields (DDFs) will focus on the edges among adjacent tissues when the segmentation labels are directly used to drive the registration progress, which will decrease the plausibility of brain MRI registration. PURPOSE: In order to increase the accuracy of registration and ensure the plausibility of registration at the same time, we combine the local-signed-distance fields (LSDFs) and intensity images to dually supervise the registration progress. The proposed method not only uses the intensity and segmentation information but also uses the voxelwise geometric distance information to the edges. Hence, the accurate voxelwise correspondence relationships are guaranteed both inside and outside the edges. METHODS: The proposed dually-supervised registration method mainly includes three enhancement strategies. Firstly, we leverage the segmentation labels to construct their LSDFs to provide more geometrical information for guiding the registration process. Secondly, to calculate LSDFs, we construct an LSDF-Net, which is composed of 3D dilation layers and erosion layers. Finally, we design the dually-supervised registration network (VMLSDF ) by combining the unsupervised VoxelMorph (VM) registration network and the weakly-supervised LSDF-Net, to utilize intensity and LSDF information, respectively. RESULTS: In this paper, experiments were then carried out on four public brain image datasets: LPBA40, HBN, OASIS1, and OASIS3. The experimental results show that the Dice similarity coefficient (DSC) and 95% Hausdorff distance (HD) of VMLSDF are higher than those of the original unsupervised VM and the dually-supervised registration network (VMseg ) using intensity images and segmentation labels. At the same time, the percentage of negative Jacobian determinant (NJD) of VMLSDF is lower than VMseg . Our code is freely available at https://github.com/1209684549/LSDF. CONCLUSIONS: The experimental results show that LSDFs can improve the registration accuracy compared with VM and VMseg , and enhance the plausibility of the DDFs compared with VMseg .

The value of bile acid spectrum in the evaluation of hepatic injury in children with infectious mononucleosis caused by Epstein Barr virus infection.

Background: Infectious mononucleosis (IM) is an acute infectious disease, caused by Epstein-Barr virus (EBV) infection, which can invade various systemic systems, among which hepatic injury is the most common. In this study, ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to detect serum bile acid spectrum in IM children quantitatively, and to investigate its role in the early assessment of hepatic injury. Methods: This case-control study was conducted at Yuhuan People's Hospital. A total of 60 IM children and 30 healthy children were included in the study. Among 60 children with IM, 30 had hepatic injury, and 30 without hepatic injury. The clinical and laboratory data were analyzed, and the serum bile acid spectrum and lymphocyte subsets were evaluated in the three groups. Results: There were statistically significant differences in cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid(GDCA), glycolithocholic acid (GLCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid(TUDCA), percentage of NK cells, CD4+ and CD8+ in IM hepatic injury group, without hepatic injury group, and the healthy control group (P < 0.05). The percentage of NK cells was positively correlated with TCA (P < 0.05); it was negatively correlated with CDCA, DCA, LCA, GCDCA, GDCA, GLCA, TDCA, UDCA, GUDCA, TUDCA (P < 0.05). CD4+ was positively correlated with CA, TCA and TCDCA (P < 0.05); it was negatively correlated with CDCA, DCA, LCA, GCDCA, GDCA, GLCA, TDCA, UDCA, GUDCA and TUDCA (P < 0.05). CD8+ was positively correlated with CDCA, DCA, LCA, GCDCA, GDCA, GLCA, TDCA, UDCA, GUDCA and TUDCA (P < 0.05); it was negatively correlated with CA, TCA and TCDCA (P < 0.05). ROC curve analysis showed that CD8+, GDCA and GLCA had high predictive value for hepatic injury in IM patients. Conclusions: UPLC-MS/MS method can sensitively detect the changes in serum bile acid spectrum before hepatic injury in children with IM, which is helpful for early assessment of hepatic injury in children with IM. The changes in lymphocyte subsets in IM children are related to some bile acid subfractions, which may be related to IM hepatic injury.

Size Effect on the Post-Necking Behaviour of Dual-Phase 800 Steel: Modelling and Experiment.

This work investigated the feasibility of using a miniaturised non-standard tensile specimen to predict the post-necking behaviour of the materials manufactured via a rapid alloy prototyping (RAP) approach. The experimental work focused on the determination of the Lankford coefficients (r-value) of dual-phase 800 (DP800) steel and the digital image correlation (DIC) for some cases, which were used to help calibrate the damage model parameters of DP800 steel. The three-dimensional numerical simulations focused on the influence of the size effect (aspect ratio, AR) on the post-necking behaviour, such as the strain/stress/triaxiality evolutions, fracture angles, and necking mode transitions. The modelling showed that although a good correlation can be found between the predicted and experimentally observed ultimate tensile strength (UTS) and total elongation. The standard tensile specimen with a gauge length of 80 mm exhibited a fracture angle of ∼55°, whereas the smaller miniaturised non-standard specimens with low ARs exhibited fractures perpendicular to the loading direction. This shows that care must be taken when comparing the post-necking behaviour of small-scale tensile tests, such as those completed as a part of a RAP approach, to the post-necking behaviours of standard full-size test specimens. However, the modelling work showed that this behaviour is well represented, demonstrating a transition between the fracture angles of the samples between 2.5 and 5. This provides more confidence in understanding the post-necking behaviour of small-scale tensile tests.

Structural MRI Harmonization via Disentangled Latent Energy-Based Style Translation.

Multi-site brain magnetic resonance imaging (MRI) has been widely used in clinical and research domains, but usually is sensitive to non-biological variations caused by site effects (e.g., field strengths and scanning protocols). Several retrospective data harmonization methods have shown promising results in removing these non-biological variations at feature or whole-image level. Most existing image-level harmonization methods are implemented through generative adversarial networks, which are generally computationally expensive and generalize poorly on independent data. To this end, this paper proposes a disentangled latent energy-based style translation (DLEST) framework for image-level structural MRI harmonization. Specifically, DLEST disentangles site-invariant image generation and site-specific style translation via a latent autoencoder and an energy-based model. The autoencoder learns to encode images into low-dimensional latent space, and generates faithful images from latent codes. The energy-based model is placed in between the encoding and generation steps, facilitating style translation from a source domain to a target domain implicitly. This allows highly generalizable image generation and efficient style translation through the latent space. We train our model on 4,092 T1-weighted MRIs in 3 tasks: histogram comparison, acquisition site classification, and brain tissue segmentation. Qualitative and quantitative results demonstrate the superiority of our approach, which generally outperforms several state-of-the-art methods.

Brain Anatomy-Guided MRI Analysis for Assessing Clinical Progression of Cognitive Impairment with Structural MRI.

Brain structural MRI has been widely used for assessing future progression of cognitive impairment (CI) based on learning-based methods. Previous studies generally suffer from the limited number of labeled training data, while there exists a huge amount of MRIs in large-scale public databases. Even without task-specific label information, brain anatomical structures provided by these MRIs can be used to boost learning performance intuitively. Unfortunately, existing research seldom takes advantage of such brain anatomy prior. To this end, this paper proposes a brain anatomy-guided representation (BAR) learning framework for assessing the clinical progression of cognitive impairment with T1-weighted MRIs. The BAR consists of a pretext model and a downstream model, with a shared brain anatomy-guided encoder for MRI feature extraction. The pretext model also contains a decoder for brain tissue segmentation, while the downstream model relies on a predictor for classification. We first train the pretext model through a brain tissue segmentation task on 9,544 auxiliary T1-weighted MRIs, yielding a generalizable encoder. The downstream model with the learned encoder is further fine-tuned on target MRIs for prediction tasks. We validate the proposed BAR on two CI-related studies with a total of 391 subjects with T1-weighted MRIs. Experimental results suggest that the BAR outperforms several state-of-the-art (SOTA) methods. The source code and pre-trained models are available at https://github.com/goodaycoder/BAR.

Circ-CREBBP promotes cell tumorigenesis and glutamine catabolism in glioma by regulating miR-375/glutaminase axis.

Circular RNA CREB-binding protein (circ-CREBBP) has been reported to involve in the tumorigenesis of glioma. However, the role and underlying molecular mechanism of circ-CREBBP in glioma glutamine catabolism remain unclear. The expression of circ-CREBBP, microRNA (miR)-375 and glutaminase (GLS) was detected using quantitative real-time polymerase chain reaction and western blot. The 3­(4, 5­dimethylthiazol­2­y1)­2, 5­diphenyl tetrazolium bromide (MTT), colony formation, flow cytometry and transwell assays were used to determine the effects of them on glioma cell malignant biological behaviors in vitro. Glutamine metabolism was analyzed using assay kits. Murine xenograft model was established to investigate the role of circ-CREBBP in vivo. The binding interactions between miR-375 and circ-CREBBP or GLS were confirmed by the dual-luciferase reporter assay. Circ-CREBBP was highly expressed in glioma tissues and cells, and high expression of circ-CREBBP predicted poor prognosis. Circ-CREBBP knockdown suppressed cell proliferation, migration, invasion and glutamine metabolism while expedited cell apoptosis in glioma in vitro, as well as impeded tumor growth in vivo. Circ-CREBBP directly targeted miR-375, which was demonstrated to restrain glioma cell growth, motility and glutamine metabolism. Moreover, miR-375 inhibition reverted the anticancer effects of circ-CREBBP knockdown on glioma cells. GLS was a target of miR-375, GLS silencing or the treatment of GLS inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) impaired glioma cell malignant phenotypes and glutamine metabolism. Importantly, GLS up-regulation weakened the tumor-suppressive functions of miR-375 on glioma cells. Mechanistically, circ-CREBBP indirectly regulated GLS expression through sponging miR-375. In all, circ-CREBBP expedited glioma tumorigenesis and glutamine metabolism through miR-375/GLS axis, suggesting a promising target for combined glioma therapy.

UPLC-MS/MS Assay for Quantification of Wedelolactone and Demethylwedelolactone in Rat Plasma and the Application to a Preclinical Pharmacokinetic Study.

AIMS AND OBJECTIVE: Wedelolactone and demethylwedelolactone are the two major coumarin constituents of Herba Ecliptae. The objective of this work was to develop and validate a sensitive, rapid, and robust UPLC-MS/MS method for the simultaneous quantification of wedelolactone and demethylwedelolactone in rat plasma. MATERIALS AND METHODS: Wedelolactone and demethylwedelolactone were extracted from rat plasma by protein precipitation with acetonitrile. Electrospray ionization in negative mode and selected reaction monitoring (SRM) were used for wedelolactone and demethylwedelolactone at the transitions m/z 312.8→298.0 and m/z 299.1→270.6, respectively. Chromatographic separation was conducted on a Venusil C18 column (50 mm × 2.1 mm, 5 µm) with isocratic elution of acetonitrile-0.1% formic acid in water (55:45, v/v) at a flow rate of 0.3 mL/min. A linear range was observed over the concentration range of 0.25-100 ng/mL for wedelolactone and demethylwedelolactone. RESULTS: They reached their maximum plasma concentrations (Cmax, 74.9±13.4 ng/mL for wedelolactone and 41.3±9.57 ng/mL for demethylwedelolactone) at the peak time (Tmax) of 0.633 h and 0.800 h, respectively. The AUC0-t value of wedelolactone (260.8±141.8 ng h/mL) was higher than that of demethylwedelolactone (127.4±52.7 ng h/mL) by approximately 2-fold, whereas the terminal elimination half-life (t1/2) of wedelolactone (2.20±0.59 h) showed the approximately same as that of demethylwedelolactone (2.08±0.69 h). CONCLUSION: Based on full validation according to US FDA guidelines, this UPLC-MS/MS method was successfully applied to a pharmacokinetic study in rats.