State-Dependent Effective Connectivity in Resting-State fMRI.

The human brain at rest exhibits intrinsic dynamics transitioning among the multiple metastable states of the inter-regional functional connectivity. Accordingly, the demand for exploring the state-specific functional connectivity increases for a deeper understanding of mental diseases. Functional connectivity, however, lacks information about the directed causal influences among the brain regions, called effective connectivity. This study presents the dynamic causal modeling (DCM) framework to explore the state-dependent effective connectivity using spectral DCM for the resting-state functional MRI (rsfMRI). We established the sequence of brain states using the hidden Markov model with the multivariate autoregressive coefficients of rsfMRI, summarizing the functional connectivity. We decomposed the state-dependent effective connectivity using a parametric empirical Bayes scheme that models the effective connectivity of consecutive windows with the time course of the discrete states as regressors. We showed the plausibility of the state-dependent effective connectivity analysis in a simulation setting. To test the clinical applicability, we applied the proposed method to characterize the state- and subtype-dependent effective connectivity of the default mode network in children with combined-type attention deficit hyperactivity disorder (ADHD-C) compared with age-matched, typically developed children (TDC). All 88 children were subtyped according to the occupation times (i.e., dwell times) of the three dominant functional connectivity states, independently of clinical diagnosis. The state-dependent effective connectivity differences between ADHD-C and TDC according to the subtypes and those between the subtypes of ADHD-C were expressed mainly in self-inhibition, magnifying the importance of excitation inhibition balance in the subtyping. These findings provide a clear motivation for decomposing the state-dependent dynamic effective connectivity and state-dependent analysis of the directed coupling in exploring mental diseases.

Empirical Bayes estimation of pairwise maximum entropy model for nonlinear brain state dynamics.

The pairwise maximum entropy model (pMEM) has recently gained widespread attention to exploring the nonlinear characteristics of brain state dynamics observed in resting-state functional magnetic resonance imaging (rsfMRI). Despite its unique advantageous features, the practical application of pMEM for individuals is limited as it requires a much larger sample than conventional rsfMRI scans. Thus, this study proposes an empirical Bayes estimation of individual pMEM using the variational expectation-maximization algorithm (VEM-MEM). The performance of the VEM-MEM is evaluated for several simulation setups with various sample sizes and network sizes. Unlike conventional maximum likelihood estimation procedures, the VEM-MEM can reliably estimate the individual model parameters, even with small samples, by effectively incorporating the group information as the prior. As a test case, the individual rsfMRI of children with attention deficit hyperactivity disorder (ADHD) is analyzed compared to that of typically developed children using the default mode network, executive control network, and salient network, obtained from the Healthy Brain Network database. We found that the nonlinear dynamic properties uniquely established on the pMEM differ for each group. Furthermore, pMEM parameters are more sensitive to group differences and are better associated with the behavior scores of ADHD compared to the Pearson correlation-based functional connectivity. The simulation and experimental results suggest that the proposed method can reliably estimate the individual pMEM and characterize the dynamic properties of individuals by utilizing empirical information of the group brain state dynamics.

Anti­angiogenic effect of mountain ginseng in vitro and in vivo: Comparison with farm­cultivated ginseng.

Mountain ginseng (Panax ginseng) has been used for cancer patient therapy in Northeast Asia. Although it is well known that cancer cells are able to induce angiogenesis, the effect of mountain ginseng on angiogenesis is still unknown. In the present study, we investigated whether ethanolic extract of mountain ginseng (MGE) could inhibit angiogenesis in in vitro and in vivo models. In comparison with farm­cultivated ginseng extract (FGE), MGE more strongly inhibited cell migration and formation of capillary­like network within non­cytotoxic ranges in SVEC4­10 cells. In addition, MGE dose­dependently suppressed Transwell cell migration of the cells. Moreover, MGE reduced the phosphorylation and expression of VEGF­R2 as well as the phosphorylation of FAK, Src, Akt and ERK, the intermediate proteins in the VEGF­R2 signaling cascade, in the cells. As expected, MGE dramatically decreased hemoglobin content in Matrigel plugs in mice. In conclusion, MGE possesses stronger anti­angiogenic properties than FGE in vascular endothelial cells. Such effect of MGE is correlated with inhibition of activation of the VEGF­R2 signaling pathway. Therefore, the novel features of MGE may be helpful for understanding its anticancer mechanism for the treatment of cancer patients.

Mountain ginseng inhibits skeletal muscle atrophy by decreasing muscle RING finger protein-1 and atrogin1 through forkhead box O3 in L6 myotubes.

ETHNOPHARMACOLOGICAL RELEVANCE: Mountain ginseng (Panax ginseng C.A. Meyer) is a medicinal herb with immune effects, muscle damage protection and energy metabolism effects. However, the pharmacological role of mountain ginseng in dexamethasone (DEXA)-induced muscle atrophy through the forkhead box O (FOXO) family is not understood. Therefore, we hypothesized that mountain ginseng inhibits skeletal muscle atrophy by decreasing muscle RING finger protein-1 (MuRF1) and atrogin1 through FOXO3 in L6 myotubes. METHODS: Rat myoblast (L6) cells or Sprague-Dawley (SD) rats were exposed to DEXA and mountain ginseng. The expressions of muscle atrophy targets such as MuRF1, atrogin1, MyHC (myosin heavy chain), HSP90, p-Akt, Akt, p-ERK1/2, ERK, FOXO3a, FOXO1, myostatin, and follistatin were analyzed by using Western blot analysis or real-time PCR. The diameter of myotubes was measured. Recruitment of glucocorticoid receptor (GR) or FOXO3a was analyzed by performing a chromatin immunoprecipitation (ChIP) assay. RESULTS: Mountain ginseng treatment reduced muscle weight loss and collagen deposition in DEXA-induced rats. Mountain ginseng treatment led to decreases in MuRF1, atrogin1, p-ERK1/2, FOXO3a, FOXO1, and myostatin. Also, mountain ginseng treatment led to increases in the diameter of myotubes, MyHC, HSP90, p-Akt, and follistatin. Treatment with mountain ginseng reduced enrichment of GR, FOXO3a, and RNA polymerase II on the promoters. CONCLUSIONS: These results suggest that mountain ginseng inhibits skeletal muscle atrophy by decreasing MuRF1 and atrogin1 through FOXO3a in L6 myotubes.

Anticancer Effect of Mountain Ginseng on Human Breast Cancer: Comparison with Farm-Cultivated Ginseng.

Mountain ginseng has been used generally as a pharmacopuncture for cancer therapy in clinical practice in Northeast Asia. Nonetheless, there have been few scientific reports for the anticancer action of mountain ginseng. In this study, we investigated whether mountain ginseng extract (MGE) could inhibit the growth of breast cancer in in vitro and in vivo models. MGE showed stronger cytotoxicity than farm-cultivated ginseng extract (FGE) through promoting ROS generation. Also MGE dose-dependently brought about mitochondrial dysfunction in MCF-7 cells. In addition, MGE induced apoptosis through enhancing the activities of caspase-3/7 by regulation of expression of Bcl-2, Bax, cytochrome c, and cleaved caspase-3 in the MCF-7 cells. Consistent with the in vitro results, MGE significantly reduced tumor weights compared with FGE in mice transplanted with MCF-7 cells, and it regulated the expression of apoptosis-related proteins, such as Bcl-2, Bax, cytochrome c, cleaved caspase-3, and cleaved PARP, in the tumor tissues. Additionally, MGE included higher total ginsenoside contents than FGE. In conclusion, MGE, which is richer in ginsenosides, exerts a stronger anticancer action than FGE in breast cancer. The anticancer action of MGE may be closely correlated with caspase-mediated apoptosis through upregulating ROS generation. Therefore, these findings may be helpful for a clinical understanding of the anticancer mechanism of MGE for breast cancer patients.

Dynamic causal modeling of hippocampal activity measured via mesoscopic voltage-sensitive dye imaging.

The aim of this paper is to present a dynamic causal modeling (DCM) framework for hippocampal activity measured via voltage-sensitive dye imaging (VSDI). We propose a DCM model of the hippocampus that summarizes interactions between the hilus, CA3 and CA1 regions. The activity of each region is governed via a neuronal mass model with two inhibitory and one/two excitatory neuronal populations, which can be linked to measurement VSDI by scaling neuronal activity. To optimize the model structure for the hippocampus, we propose two Bayesian schemes: Bayesian hyperparameter optimization to estimate the unknown electrophysiological properties necessary for constructing a mesoscopic hippocampus model; and Bayesian model reduction to determine the parameterization of neural properties, and to test and include potential connections (morphologically inferred without direct evidence yet) in the model by evaluating group-level model evidence. The proposed method was applied to model spatiotemporal patterns of accumulative responses to consecutive stimuli in separate groups of wild-type mice and epileptic aristaless-related homeobox gene (Arx) conditional knock-out mutant mice (Arx-/+;Dlx5/6CRE-IRES-GFP) in order to identify group differences in the effective connectivity within the hippocampus. The causal role of each group-differing connectivity in generating mutant-like responses was further tested. The group-level analysis identified altered intra- and inter-regional effective connectivity, some of which are crucial for explaining mutant-like responses. The modelling results for the hippocampal activity suggest the plausibility of the proposed mesoscopic hippocampus model and the usefulness of utilizing the Bayesian framework for model construction in the mesoscale modeling of neural interactions using DCM.

Practical Inter-Floor Noise Sensing System with Localization and Classification.

Inter-floor noise is a severe social problem which causes illegal arson, violence, and even murder. In this paper, an inter-floor noise sensing system is proposed to detect and record information related to inter-floor noise in an apartment building. The proposed system measured the noise level and estimated the direction of the noise source along with the type of noise. The noise level measurement is based on the sound pressure level (SPL) measurement, which is a logarithmic measure of the effective pressure of a sound relative to a reference sound pressure. Noise source localization was performed using the estimated time difference of arrival (TDOA) from the microphone array. For the classification of noise types, the Mel frequency cepstral coefficients (MFCC) and zero-crossing rate (ZCR) were extracted from a noise signal, and the k-nearest neighbor algorithm was used to classify the type of noise. In addition, we developed a noise monitoring hardware to evaluate our methods in the actual environment. The experimental results demonstrated that the proposed system had a reliable accuracy for each functional unit. The results showed that the error of the noise level was approximately ±1.5 dB(A), the error of the direction estimation was approximately ±10°, and the accuracy of the classification for the noise type was more than 75%. These output data from the proposed system are expected to be used as important reference data for any dispute cases due to inter-floor noise.

Potent anti-aging activity of Aruncus dioicus, a native plant of Ulleung-do, South Korea, in CCD-986sk fibroblasts via suppression of matrix metalloproteinases.

Aruncus dioicus var. kamtschaticus HARA, also known as goat's beard, is a native plant in Ulleung-do, South Korea. It has been used as a remedy in skin care, detoxification, blood stanching, tonsillitis. High performance liquid chromatography with diode array detection was used for partial validation of bioactive chemicals in A. dioicus ethyl acetate (EtOAc) extract, and EtOAC extract was examined for its effect on ultraviolet (UV)-induced cell aging using CCD-986sk-human skin fibroblast cells. Cells were exposed to UV-B for 1 min before extract treatment. An established viability assay was performed to test cell toxicity of A. dioicus at 5, 10, or 50 µg/ml concentrations, and activities of matrix metalloproteinase (MMP) 1, 2, 3, phosphorylated-p38 (p-p38, an activated form of p38), p38, and c-fos transcription factors were evaluated. A. dioicus extract decreased the amount of mRNA transcripts and total proteins of MMP1, 2, 3 as well as p-p38 and c-fos. The c-fos expression was also confirmed by in vivo fluorescent staining of CCD-986sk cells after UV-B exposure followed by EtOAc extract treatment. The results showed that expression of skin aging related genes encoding MMP1, 2, and 3 was inhibited by reduced transcription factor expression of p-p38 and c-fos by A. dioicus EtOAc extract. The results suggest that A. dioicus extract can be used to reduce UV-B-induced skin aging and is a potential candidate for cosmedical materials.

Suppression of mast-cell-mediated allergic inflammation by Lindera obtusiloba.

Allergic disease is a consequence of exposure to normally innocuous substances that elicit the activation of mast cells. Mast-cell-mediated allergic response is involved in many diseases such as anaphylaxis, allergic rhinitis, asthma and atopic dermatitis. The discovery of drugs for the treatment of allergic disease is an important subject in human health. In this study, we investigated the effect of Lindera obtusiloba water extract (LOWE) on the mast-cell-mediated allergic inflammation and possible mechanism of action using in vitro and in vivo models. LOWE reduced histamine release from various types of mast cells activated by immunoglobulin E (IgE) or phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI). The inhibitory effect of LOWE on histamine release was mediated by calcium signal. LOWE decreased the PMACI-stimulated gene expression of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in human mast cells. The inhibitory effect of LOWE on the proinflammatory cytokines was nuclear factor (NF)-κB dependent. In addition, LOWE suppressed compound 48/80-induced systemic allergic reaction and serum histamine release in mice and IgE-mediated local allergic reactions. Our results indicate that LOWE inhibits mast-cell-derived allergic inflammation and involvement of calcium, histamine, proinflammatory cytokines and NF-κB in these effects.

Physiological activity of irradiated green tea polyphenol on the human skin.

Physiological activity of irradiated green tea polyphenol on the human skin was investigated for further industrial application. The green tea polyphenol was separated and irradiated at 40 kGy by y-ray. For an anti-wrinkle effect, the collagenase inhibition effect was higher in the irradiated sample (65.3%) than that of the non-irradiated control (56.8%) at 200 ppm of the concentration (p < 0.05). Collagen biosynthesis rates using a human fibroblast were 19.4% and 16.3% in the irradiated and the non-irradiated polyphenols, respectively. The tyrosinase inhibition effect, which is related to the skin-whitening effect, showed a 45.2% and 42.9% in the irradiated and the non-irradiated polyphenols, respectively, at a 100 ppm level. A higher than 90% growth inhibition on skin cancer cells (SK-MEL-2 and G361) was demonstrated in both the irradiated and the non-irradiated polyphenols. Thus, the irradiation of green tea polyphenol did not change and even increased its anti-wrinkle, skin-whitening and anticancer effects on the human skin. The results indicated that irradiated green tea polyphenol can be used as a natural ingredient with excellent physiological functions for the human skin through cosmetic or food composition.

Inhibition of enzyme activities and the antiwrinkle effect of polyphenol isolated from the persimmon leaf (Diospyros kaki folium) on human skin.

BACKGROUND: Many studies have been conducted to find a natural material that has high biologic functions for human skin without any side effects. Persimmon leaf has a substantial amount of tannins in different forms; therefore, it was selected as a target material. OBJECTIVE: The biosynthesis rate of the collagen was also investigated to clarify the beneficial functions for the human skin. METHODS: Persimmon leaves were obtained, extracted with 80% ethanol, and isolated into PFs I, II, and III after column chromatography using a Sephadex LH-20 column followed by thin-layer chromatography. RESULTS: The xanthine oxidase inhibition effect of both PFs II and III was over 40% at a 100 ppm concentration. PF II, containing higher flavonoids levels, had a significantly higher tyrosinase inhibition than that of PF III. Collagenase inhibition was 16.3 and 8.1% for PF III and PF II, respectively, at 100 ppm. On the other hand, elastase inhibition activity was significantly higher in PF II than PF III. Collagen biosynthesis rates of PF III were over 25% from a 1 to 10 ppm concentration. Consequently, PFs isolated from the persimmon leaf can be used as natural materials or additives for human skin owing to their beneficial biologic functions, including the antiwrinkle effect and the inhibition of skin problems, for food or cosmetic compositions.