Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-ß/Smad2/3 pathway.

Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is downregulated in liver cancer tissues, which correlates with poor patient survival. Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers. A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues. Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis. TMEFF1 transcription is activated by Parkin-induced endogenous TGF-ß production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-ß inhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers. Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1ß and p53, which accounts for the suppression of TGF-ß production. Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-ß/Smad2/3 pathway, resulting in the expression of TMEFF1 which promotes cell migration, EMT, and metastasis in liver cancer cells.

The neural origin for asymmetric coding of surface color in the primate visual cortex.

The coding privilege of end-spectral hues (red and blue) in the early visual cortex has been reported in primates. However, the origin of such bias remains unclear. Here, we provide a complete picture of the end-spectral bias in visual system by measuring fMRI signals and spiking activities in macaques. The correlated end-spectral biases between the LGN and V1 suggest a subcortical source for asymmetric coding. Along the ventral pathway from V1 to V4, red bias against green peaked in V1 and then declined, whereas blue bias against yellow showed an increasing trend. The feedforward and recurrent modifications of end-spectral bias were further revealed by dynamic causal modeling analysis. Moreover, we found that the strongest end-spectral bias in V1 was in layer 4C[Formula: see text]. Our results suggest that end-spectral bias already exists in the LGN and is transmitted to V1 mainly through the parvocellular pathway, then embellished by cortical processing.

Dynamic Recruitment of the Feedforward and Recurrent Mechanism for Black-White Asymmetry in the Primary Visual Cortex.

Black and white information is asymmetrically distributed in natural scenes, evokes asymmetric neuronal responses, and causes asymmetric perceptions. Recognizing the universality and essentiality of black-white asymmetry in visual information processing, the neural substrates for black-white asymmetry remain unclear. To disentangle the role of the feedforward and recurrent mechanisms in the generation of cortical black-white asymmetry, we recorded the V1 laminar responses and LGN responses of anesthetized cats of both sexes. In a cortical column, we found that black-white asymmetry starts at the input layer and becomes more pronounced in the output layer. We also found distinct dynamics of black-white asymmetry between the output layer and the input layer. Specifically, black responses dominate in all layers after stimulus onset. After stimulus offset, black and white responses are balanced in the input layer, but black responses still dominate in the output layer. Compared with that in the input layer, the rebound response in the output layer is significantly suppressed. The relative suppression strength evoked by white stimuli is notably stronger and depends on the location within the ON-OFF cortical map. A model with delayed and polarity-selective cortical suppression explains black-white asymmetry in the output layer, within which prominent recurrent connections are identified by Granger causality analysis. In addition to black-white asymmetry in response strength, the interlaminar differences in spatial receptive field varied dynamically. Our findings suggest that the feedforward and recurrent mechanisms are dynamically recruited for the generation of black-white asymmetry in V1.SIGNIFICANCE STATEMENT Black-white asymmetry is universal and essential in visual information processing, yet the neural substrates for cortical black-white asymmetry remain unknown. Leveraging V1 laminar recordings, we provided the first laminar pattern of black-white asymmetry in cat V1 and found distinct dynamics of black-white asymmetry between the output layer and the input layer. Comparing black-white asymmetry across three visual hierarchies, the LGN, V1 input layer, and V1 output layer, we demonstrated that the feedforward and recurrent mechanisms are dynamically recruited for the generation of cortical black-white asymmetry. Our findings not only enhance our understanding of laminar processing within a cortical column but also elucidate how feedforward connections and recurrent connections interact to shape neuronal response properties.

Meroterpenoids from Ganoderma petchii inhibiting migration of triple negative breast cancer cells.

Ganoderpetchoids A-E and (-)-dayaolingzhiol H, six undescribed meroterpenoids, were isolated from Ganoderma petchii. Their structures including the relative configurations were identified by means of spectroscopic methods and 13C NMR calculations. Chiral separation of the new racemics was performed to afford their respective enantiomers. The absolute configurations of the new isolates were clarified by computational approaches, CD comparisons and X-ray diffraction analysis. Biological studies toward triple negative breast cancer indicated that (+)-6 and (-)-6 significantly inhibit the migration of MDA-MB-231 cell line.

Complex Oligomers and their Bioactivity of Annonaceae Family.

BACKGROUND: A series of novel oligomers with various types and complex skeletons are isolated from Annonaceae plants, which displayed anti-inflammatory, antimalarial, antibacterial and other biological activities. Thus, their structures and functions have received more and more attention. AIM AND OBJECTIVE: The purpose of this review is to provide a systematic reference for chemical structures and biological activities of oligomers and some clues for finding more analogues from Annonaceae. METHODS: Publications relevant to Annonaceae were retrieved from the Web of Science and SciFinder and surveyed for a literature review. RESULTS: This article summarized the chemical structures, the base source plants and the biofunctions of oligomers from Annonaceae. CONCLUSION: The oligomers from Annonaceae have the characteristics of various connection modes and rich functional groups, which provides more possibilities for the discovery of lead compounds with new or higher biological activities.

Antioxidation Abilities of Sesquiterpenoids from Curcuma aromatica in vitro.

AIMS AND OBJECTIVES: In our previous study, 21 sesquiterpenoids with different skeleton types were isolated from the radix of Curcuma aromatica Salisb., a traditional Chinese medicine used for treating depression and qi and blood stasis. C. aromatica enhanced PC12 cell viability upon damage by H2O2. The aim of this study was to elucidate the antioxidation capability of these sesquiterpenoids using a model of H2O2-induced PC12 cells and analyze the correlation between their structure and bio-activity. MATERIALS AND METHODS: PC12 cells were simultaneously treated with 400 µM H2O2 and sesquiterpenoid compounds or vitamin E (used as a positive control) for 24 h. The activities of GSH-Px, LDH, CAT, and SOD were detected by ELISA kits. The reactive oxygen species (ROS) level in the cells was determined by the fluorescence probe DCFH-DA. [Ca2+]i was detected based on the Fluo 2-AM fluorescence labeling assay. The structures of sesquiterpenoids were featured with 41 selected molecular descriptors, and the relationship between active parameters and structural features was determined by the partial least squares (PLS) analysis. RESULTS: All twenty-one sesquiterpenoids from the radix of C. aromatica increased the activities of GSH-Px, CAT, and SOD, and decreased the LDH leakage, and levels of ROS level and [Ca2+]i to different degrees. Some relationships were observed between the molecular descriptors featured by the sesquiterpenoids and GSH-Px, CAT, SOD, LDH, ROS, and [Ca2+]i by PLS analysis. CONCLUSIONS: Twenty-one sesquiterpenoids showed different antioxidation abilities as measured by a model of H2O2-induced PC12 cells. Five molecular descriptors were positively correlated with GSH-Px, CAT, SOD, and were negatively correlated with LDH and [Ca2+].

Two new sesquiterpenes from Xylopia vielana.

Two new sesquiterpenes (1-2) and six known analogues (3-8) were isolated from the branches and leaves of Xylopia vielana Pierre. The structures of the new compounds were identified by analyzing 1 D and 2 D NMR data and HRESIMS data, combined with induced and calculated circular dichroism experiments. In addition, compounds 1-4, 7 and 8 showed notable nitric oxide (NO) inhibitory effects (IC50 < 10 µM) on the model of the lipopolysaccharide (LPS)-activated RAW 264.7 macrophages.

V1-bypassing suppression leads to direction-specific microsaccade modulation in visual coding and perception.

Microsaccades play a critical role in refreshing visual information and have been shown to have direction-specific influences on human perception. However, the neural mechanisms underlying such direction-specific effects remains unknown. Here, we report the emergence of direction-specific microsaccade modulation in the middle layer of V2 but not in V1: responses of V2 neurons after microsaccades moved toward their receptive fields were stronger than those when microsaccades moved away. The decreased responses from V1 to V2, which are correlated with the amplitude of microsaccades away from receptive fields, suggest topographically location-specific suppression from an oculomotor source. Consistent with directional effects in V2, microsaccades function as a guide for monkeys' behavior in a peripheral detection task; both can be explained by a dynamic neural network. Our findings suggest a V1-bypassing suppressive circuit for direction-specific microsaccade modulation in V2 and its functional influence on visual sensitivity, which highlights the optimal sampling nature of microsaccades.

Cascaded normalizations for spatial integration in the primary visual cortex of primates.

Spatial integration of visual information is an important function in the brain. However, neural computation for spatial integration in the visual cortex remains unclear. In this study, we recorded laminar responses in V1 of awake monkeys driven by visual stimuli with grating patches and annuli of different sizes. We find three important response properties related to spatial integration that are significantly different between input and output layers: neurons in output layers have stronger surround suppression, smaller receptive field (RF), and higher sensitivity to grating annuli partially covering their RFs. These interlaminar differences can be explained by a descriptive model composed of two global divisions (normalization) and a local subtraction. Our results suggest suppressions with cascaded normalizations (CNs) are essential for spatial integration and laminar processing in the visual cortex. Interestingly, the features of spatial integration in convolutional neural networks, especially in lower layers, are different from our findings in V1.

Response of Properties and Chemicals to Preparation Parameters in the Oxidation Processing of Refined Montan Wax.

Refined montan wax (RMW) is a lignite-based chemical product with wide application and high added value. However, research on its processing and performance is very limited. Currently, four parameters in the key preparation procedure for the oxidation bleaching of RMW, including the concentration of two oxidants (H2SO4 (P1) and CrO3 (P2)), oxidation time (P3), and the mass ratio of CrO3 used in two oxidation steps (P4), were systematically evaluated in regard to their impact on the properties and chemistry of RMW. The results showed that the four tested parameters visibly affected RMW, and each parameter had a different impact on the properties of RMW by range analysis, of which P1 showed a greater influence on its acid value; P2 influenced its friability, specific surface area, and aperture; P3 affected its color, initial melting point, and saponification value; and P4 had a higher impact on its final melting point, melting range, and hardness. Gas chromatography with flame ionization detection-mass spectrometry analysis revealed that the compounds found in RMW samples (RMWs) under different oxidation conditions differed significantly, with major differences in the content and amount of these components. Among the compounds in RMWs, 16 different compounds (variable importance of projection > 1) were found by the orthogonal projections to latent structures discriminant analysis method, nine of which have a strong relationship to the different performances of RMWs. This work provided a basis for the development of performance-oriented preparation processing technology for RMW.

Coding strategy for surface luminance switches in the primary visual cortex of the awake monkey.

Both surface luminance and edge contrast of an object are essential features for object identification. However, cortical processing of surface luminance remains unclear. In this study, we aim to understand how the primary visual cortex (V1) processes surface luminance information across its different layers. We report that edge-driven responses are stronger than surface-driven responses in V1 input layers, but luminance information is coded more accurately by surface responses. In V1 output layers, the advantage of edge over surface responses increased eight times and luminance information was coded more accurately at edges. Further analysis of neural dynamics shows that such substantial changes for neural responses and luminance coding are mainly due to non-local cortical inhibition in V1's output layers. Our results suggest that non-local cortical inhibition modulates the responses elicited by the surfaces and edges of objects, and that switching the coding strategy in V1 promotes efficient coding for luminance.

Antioxidant effects of diarylheptanoids from two Curcuma species.

Five linear diarylheptanoids (1-5), including a new one (1), were isolated from the rhizomes of Curcuma kwangsiensis S. G. Lee et C. F. Liang, while four linear diarylheptanoids (6-9) and four cyclic diarylheptanoids (10-13) were isolated from the roots of Curcuma aromatica Salisb. Using the model of H2O2-induced PC12 cells, the antioxidant effects of these thirteen diarylheptanoids from these two traditional Chinese medicines from Curcuma genus of Zingiberaceae family were investigated. As result, they produced different efficiency on damaged cell viability, ROS, LDH, SOD, CAT, and GSH-Px, which were the six indexes related to oxidative stress. Further, the correlation between these six bio-indexes and 53 selected molecular descriptors of diarylheptanoids was determined by PLS regression analysis.

The Anti-inflammatory Effects of Two Ent-kaurane Diterpenes from the Stems and Leaves of Gochnatia decora.

AIM & OBJECTIVES: The Gochnatia decora (Kurz) A. L. Cabrera is a rare woody plant belonging to the family of Asteraceae. The bark of this plant is used as a Chinese folk medicine to treat cough and pneumonia. However, the effective substance related to its efficacy remains unknown. This study aims to evaluate the potential anti-inflammatory activities of the chemicals isolated from this plant using a model of LPS-induced RAW264.7 cells. MATERIALS AND METHODS: Chemical constituents were isolated from the stems and leaves of G. decora by a series of chromatographic separation methods and identified by spectral analysis techniques. The model of inflammation in vitro was established by treatment of 1µM LPS on RAW264.7 cells. The influence of tested compounds on inflammatory factor production, including NO, TNF-α, IL-1ß, IL-6, IL-17, was determined by ELISA. The mechanisms involved were studied by western blot analysis. RESULTS: Two known ent-kaurane diterpenes (1 and 2), identified as ent-17-hydroxy-15-oxokauran- 19-oic acid (1) and ent-15α-hydroxy-16-kauran-19-oic acid (2), were isolated from the stems and leaves of G. decora. The bioassay showed that both of them produced significant inhibition of LPS-induced release of NO, TNF-α, IL-1ß, IL-6, IL-17, iNOS, and COX-2 expression. Western blot analysis showed that these two chemicals blocked LPS-induced phosphorylation of NF-κB. CONCLUSION: Compounds 1 and 2 were obtained from the genus Gochnatia.These compounds demonstrated useful anti-inflammatory activities in the model of LPS-induced RAW264.7 cells. A potential action mechanism may be the correlation of the NF-κB pathway.

Multiple gamma rhythms carry distinct spatial frequency information in primary visual cortex.

Gamma rhythms in many brain regions, including the primary visual cortex (V1), are thought to play a role in information processing. Here, we report a surprising finding of 3 narrowband gamma rhythms in V1 that processed distinct spatial frequency (SF) signals and had different neural origins. The low gamma (LG; 25 to 40 Hz) rhythm was generated at the V1 superficial layer and preferred a higher SF compared with spike activity, whereas both the medium gamma (MG; 40 to 65 Hz), generated at the cortical level, and the high gamma HG; (65 to 85 Hz), originated precortically, preferred lower SF information. Furthermore, compared with the rates of spike activity, the powers of the 3 gammas had better performance in discriminating the edge and surface of simple objects. These findings suggest that gamma rhythms reflect the neural dynamics of neural circuitries that process different SF information in the visual system, which may be crucial for multiplexing SF information and synchronizing different features of an object.

On the Optimization of a Centrifugal Maglev Blood Pump Through Design Variations.

Centrifugal blood pumps are usually designed with secondary flow paths to avoid flow dead zones and reduce the risk of thrombosis. Due to the secondary flow path, the intensity of secondary flows and turbulence in centrifugal blood pumps is generally very high. Conventional design theory is no longer applicable to centrifugal blood pumps with a secondary flow path. Empirical relationships between design variables and performance metrics generally do not exist for this type of blood pump. To date, little scientific study has been published concerning optimization and experimental validation of centrifugal blood pumps with secondary flow paths. Moreover, current hemolysis models are inadequate in an accurate prediction of hemolysis in turbulence. The purpose of this study is to optimize the hydraulic and hemolytic performance of an inhouse centrifugal maglev blood pump with a secondary flow path through variation of major design variables, with a focus on bringing down intensity of turbulence and secondary flows. Starting from a baseline design, through changing design variables such as blade angles, blade thickness, and position of splitter blades. Turbulent intensities have been greatly reduced, the hydraulic and hemolytic performance of the pump model was considerably improved. Computational fluid dynamics (CFD) combined with hemolysis models were mainly used for the evaluation of pump performance. A hydraulic test was conducted to validate the CFD regarding the hydraulic performance. Collectively, these results shed light on the impact of major design variables on the performance of modern centrifugal blood pumps with a secondary flow path.

Structurally diversified ent-kaurane and abietane diterpenoids from the stems of Tripterygium wilfordii and their anti-inflammatory activity.

Four undescribed ent-kaurane diterpenoids, wilkaunoids A - D (1-4), and three undescribed abietane diterpenoids, wilabinoids A - C (13-15), along with thirteen known ones (5-12 and 16-20), were isolated from Tripterygium wilfordii. Their structures were elucidated by extensive spectroscopic methods, electroniccirculardichroism calculation, and X-ray diffraction analysis. Compounds 1 and 2 were a pair of C-19 epimers of ent-kaurane diterpenoids, featuring a rare 19,20-epoxy-19,20-dimethoxy-kaurane fragment. Compound 3 possessed a rare naturally occurring 1,3-dioxacyclohexane moiety. Compounds 13 and 15 represented the first example of abietane diterpenoids with an isovalerate substitution from the genus of Tripterygium. The possible biosynthetic pathways of 1-3 were postulated. The effect of 1-20 on nitric oxide production was examined in lipopolysaccharide-stimulated RAW 264.7 cells. Abietane diterpenoid quinones 7-13 (IC50: 1.9-10.2 µM) exhibited the significant activity to inhibit nitric oxide production versus positive control (NG-monomethyl-l-arginine acetate salt, IC50 = 24.9 µM). The structure activity relationship of 7-13 in inhibiting nitric oxide production was then discussed. The most potent 7 and 8 were found to significantly suppress the expression of cyclooxygenase-2 and inducible nitric oxide synthase proteins, showing a good anti-inflammatory potential. The findings provided some valuable insights for the discovery and structural modification of abietane diterpenoids towards anti-inflammatory lead compounds.

The effect of microorganisms on the biomodification of montan resin from lignite.

Montan resin (MR) is an industrial by-product or solid waste generated during the production of refined montan wax and is not typically reused. In this paper, a bio-modification method using three strains of microorganisms, Acinetobacter venetianus (AV), Pseudomonas aeruginosa (PA), and Phanerochaete chrysosporium (PC), was studied to promote the performance and bio-function of MR so that MR could be recycled. MR can be degraded by these three microorganisms, and their weight loss rates were similar over the treatment period of 15 days. Compared with the original MR, the hydrophilicity of modified MRs was improved, which was related to the increase in apparent oil-water partition coefficients (Kows) and oxygen-containing and hydrophilic groups in modified MRs based on IR and GC-MS analysis. The bio-function of modified MRs by the three strains in terms of promoting maize seed germination and seedling growth was greater compared with untreated MR. Overall, these findings indicate that biomodified MRs might have useful agriculture applications.Implications: An environmentally-friendly method using microorganisms to achieve recycle of solid waste, montan resin (MR) was established in this study. Through this bio-treatment, the performance and bio-function of MR were both improved, that is the appearance and hydrophilicity of modified MRs were better than thoes in before, and the modified MRs treated by three strains showed the better promoting effects on maize seed germination and seedling growth than untreated MR, indicating the modified MRs have the certain potential of agricultural utilization in the future.

Angiogenic effects of low molecular weight organic acids present in fulvic acids of different sources.

Fulvic acid (FA) is a natural mineral medicine with a long medical history in folk. However, the active chemicals of FA remain unknown due to its diversity of sources and the complexity of compositions, which have become a bottleneck in quality control and medicinal development. Based on the traditional effect on angiogenesis, FAs from eight different coal sources were prepared and their active fractions were investigated by the CAM model, resulting that most of acetonitrile dissolved parts of these FAs (DFAs) produced angiogenesis effects. Through chemical analysis on DFAs by GC-FID/MS, six shared organic acids with low molecular weights were identified and quantified, which showed the promoting effects on capillary areas, VEGF, b-FGF, and Ang-1 at different degrees. The PCA analysis showed that the five shared organic acids with high recognition are the active chemicals in different sources of FAs which may be responsible for the angiogenesis effects.

Quinolizidine alkaloids from Sophora alopecuroides with anti-inflammatory and anti-tumor properties.

Forty-three quinolizidine alkaloids (1-43), including twelve new matrine-type ones, sophalodes A-L (1-7, 17, 19 and 28-30), were isolated from the seeds of Sophora alopecuroides. Structurally, compounds 1-4 were the first examples of C-11 oxidized matrine-type alkaloids from Sophora plants. The structures and absolute configurations of new compounds were elucidated by extensive spectroscopic techniques, X-ray diffraction analysis, and quantum chemical calculation. In addition, the NMR data and absolute configuration of compound 18 was reported for the first time. All the isolates were evaluated for their inhibition on nitric oxide production induced by lipopolysaccharide in RAW 264.7 macrophages, among them, compounds 29, 38 and 42 exhibited the most significant activity with IC50 values of 29.19, 25.86 and 33.30 µM, respectively. Further research about new compound 29 showed that it also suppressed the protein levels of iNOS and COX-2, which revealed its anti-inflammatory potential. Moreover, additional research showed that compound 16 exhibited marginal cytotoxicity against HeLa cell lines, with an IC50 value of 24.27 µM.

Superimposed gratings induce diverse response patterns of gamma oscillations in primary visual cortex.

Stimulus-dependence of gamma oscillations (GAMMA, 30-90 Hz) has not been fully understood, but it is important for revealing neural mechanisms and functions of GAMMA. Here, we recorded spiking activity (MUA) and the local field potential (LFP), driven by a variety of plaids (generated by two superimposed gratings orthogonal to each other and with different contrast combinations), in the primary visual cortex of anesthetized cats. We found two distinct narrow-band GAMMAs in the LFPs and a variety of response patterns to plaids. Similar to MUA, most response patterns showed that the second grating suppressed GAMMAs driven by the first one. However, there is only a weak site-by-site correlation between cross-orientation interactions in GAMMAs and those in MUAs. We developed a normalization model that could unify the response patterns of both GAMMAs and MUAs. Interestingly, compared with MUAs, the GAMMAs demonstrated a wider range of model parameters and more diverse response patterns to plaids. Further analysis revealed that normalization parameters for high GAMMA, but not those for low GAMMA, were significantly correlated with the discrepancy of spatial frequency between stimulus and sites' preferences. Consistent with these findings, normalization parameters and diversity of high GAMMA exhibited a clear transition trend and region difference between area 17 to 18. Our results show that GAMMAs are also regulated in the form of normalization, but that the neural mechanisms for these normalizations might differ from those of spiking activity. Normalizations in different brain signals could be due to interactions of excitation and inhibitions at multiple stages in the visual system.