Pattern Motion Direction Is Encoded in the Population Activity of Macaque Area MT.

Direction selective neurons in macaque primary visual cortex are narrowly tuned for orientation, and are thus afflicted by the aperture problem. At the next stage of motion processing, in the middle temporal (MT) area, some cells appear to solve this problem, responding to the pattern motion direction of plaids. Models have been proposed to account for this computation, but they do not replicate the diversity of responses observed in MT. We recorded from 386 cells in area MT of two male macaques, while presenting a wide range of random-line stimuli and their compositions into noise plaids. As we broadened the range of stimuli used to probe the cells, yielding ever more challenging conditions for extracting pattern motion, the diversity of the responses observed increased, and the fraction of cells that faithfully encoded pattern motion direction shrank. However, we show here that a pattern motion signal is present at the population level. We identified four mechanisms, one never proposed before, that together might account for the observed diversity in single-cell responses. Pattern motion is thus extracted in area MT, but it is encoded across the population, and not in a small subset of pattern neurons.SIGNIFICANCE STATEMENT Some neurons in the middle temporal area of macaques solve the aperture problem, signaling the direction of motion of complex patterns. As the number of pattern types used to probe this mechanism is increased, fewer and fewer cells retain this capability. We show here that different cells fail in different ways, and that simply summing their responses averages away their failures, yielding a clear pattern motion signal. Similar encodings, which unequivocally violate the "neuron as a feature detector" hypothesis that has dominated sensory processing theories for the past 50 years, might apply throughout the brain.

Sedative-Hypnotic Effects of Glycine max Merr. Extract and Its Active Ingredient Genistein on Electric-Shock-Induced Sleep Disturbances in Rats.

Glycine max Merr. (GM) is a functional food that provides many beneficial phytochemicals. However, scientific evidence of its antidepressive and sedative activities is scarce. The present study was designed to investigate the antidepressive and calmative effects of GM and its biologically active compound, genistein (GE), using electroencephalography (EEG) analysis in an electric foot shock (EFS)-stressed rat. The underlying neural mechanisms of their beneficial effects were determined by assessing corticotropin-releasing factor (CRF), serotonin (5-HT), and c-Fos immunoreactivity in the brain using immunohistochemical methods. In addition, the 5-HT2C receptor binding assay was performed because it is considered a major target of antidepressants and sleep aids. In the binding assay, GM displayed binding affinity to the 5-HT2C receptor (IC50 value of 14.25 ± 11.02 µg/mL). GE exhibited concentration-dependent binding affinity, resulting in the binding of GE to the 5-HT2C receptor (IC50, 77.28 ± 26.57 mg/mL). Administration of GM (400 mg/kg) increased non-rapid eye movement (NREM) sleep time. Administration of GE (30 mg/kg) decreased wake time and increased rapid eye movement (REM) and NREM sleep in EPS-stressed rats. In addition, treatment with GM and GE significantly decreased c-Fos and CRF expression in the paraventricular nucleus (PVN) and increased 5-HT levels in the dorsal raphe in the brain. Overall, these results suggest that GM and GE have antidepressant-like effects and are effective in sleep maintenance. These results will benefit researchers in developing alternatives to decrease depression and prevent sleep disorders.

The Correlation of Neuronal Signals with Behavior at Different Levels of Visual Cortex and Their Relative Reliability for Behavioral Decisions.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

The inhibitory effect of Cordycepin on the proliferation of cisplatin-resistant A549 lung cancer cells.

The goal of this study is to determine the anti-cancer mechanism of Cordycepin in A549 Cisplatin-Resistance (CR) lung cancer cells. Cordycepin inhibited the viability of A549CR cells in a dose-dependent manner. The cell inhibition was due to induction of apoptosis in the cells treated with Cordycepin by activation of caspase -3, -8 and -9 activities. The cell cycle analysis showed that accumulation of Sub G1 was observed in Cordycepin-treated with A549CR lung cancer cells. Based on the data of expression profile analysis of cell signaling proteins using IPS-FPAA, H-Ras was down-regulated in Cordycepin-treated A549CR cells. Collectively, anti-proliferative function of Cordycepin was due to stimulation of the cell apoptosis and the cell cycle arrest via caspases activation and down-regulation of H-Ras.

2-(4-{2-[(phenylthio)acetyl]carbonohydrazonoyl}phenoxy)acetamide as a new lead compound for management of allergic rhinitis.

OBJECTIVE: We selected a hit compound, 2-(4-{2-[(phenylthio)acetyl]-carbonohydrazonoyl}-phenoxy)acetamide (PA), by a molecular docking simulation between 636,565 compounds and caspase-1 protein. We examined the effect of PA on allergic rhinitis (AR) animal model. METHODS: We assessed the therapeutic effects and the regulatory mechanisms of ovalbumin (OVA)-sensitized mouse model of AR. RESULTS: A molecular docking simulation and a kinetic assay indicated that PA regulates the caspase-1 activation through the interaction with the caspase-1 active site. In the AR animal model, PA significantly reduced the rub scoring increased by OVA. The up-regulated IgE, histamine, interleukin (IL)-1ß, and thymic stromal lymphopoietin (TSLP) levels in the serum of OVA-sensitized mice were significantly decreased by the treatment with PA. Protein levels of IL-1ß, IL-5, IL-6, IL-13, tumor necrosis factor-α, TSLP, cyclooxygenase-2, macrophage inflammatory protein-2, and intercellular adhesion molecule-1 were also significantly inhibited by the treatment with PA in the nasal mucosa tissues of the OVA-sensitized mice. In the PA-treated mice, the number of eosinophils and mast cells infiltrated by OVA-sensitization were also reduced. In addition, PA reduced the mast cell-derived caspase-1 activity and expression in the nasal mucosa tissues of the OVA-sensitized mice. CONCLUSIONS: PA showed the possibility to regulate AR in OVA-induced AR models, suggesting that it has therapeutic potential for the management of AR as a lead compound.

Pharmacoproteomic analysis of a novel cell-permeable peptide inhibitor of tumor-induced angiogenesis.

P11, a novel peptide ligand containing a PDZ-binding motif (Ser-Asp-Val) with high affinity to integrin α(v)ß(3) was identified from a hexapeptide library (PS-SPCL) using a protein microarray chip-based screening system. Here, we investigated the inhibitory mechanism of P11 (HSDVHK) on tumor-induced angiogenesis via a pharmacoproteomic approach. P11 was rapidly internalized by, human umbilical vein endothelial cells (HUVECs) via an integrin α(v)ß(3)-mediated event. Caveolin and clathrin appeared to be involved in the P11 uptake process. The cell-penetrating P11 resulted in suppression of bFGF-induced HUVEC proliferation in a dose-dependent manner. Phosphorylation of extracellular-signal regulated kinase (ERK1/2) and mitogen-activated protein kinase kinase (MEK) in bFGF-stimulated HUVECs was inhibited by cell-permeable P11. Proteomic analysis via antibody microarray showed up-regulation of p53 in P11-treated HUVECs, resulting in induction of apoptosis via activation of caspases-3, -8, and -9. Several lines of experimental evidence strongly suggest that the molecular mechanism of P11, a novel anti-angiogenic agent, inhibits bFGF-induced HUVEC proliferation via mitogen-activated protein kinase kinase and extracellular-signal regulated kinase inhibition as well as p53-mediated apoptosis related with activation of caspases.

Inhibitory effects of NSAID-conjugated SN-38 on the viability of A549 Non-small cell lung cancer cells.

The goal of this paper was to look into the anti-tumor mechanism of Non-Steroidal Anti-Inflammatory Drug (NSAID)-conjugated SN-38 Prodrug in A549 lung cancer cells. We found that Indomethacine-SN-38 (IndoSN-38) and Naproxen-SN-38(NaproSN-38) as a theranostic prodrug targeting cyclooxygenase-2(COX-2) in cancer cells inhibited A549 cell viability in a dose-dependent fashion. IndoSN-38 and NaproSN-38 inhibited A549 cell viability in a dose-dependent fashion. The suppression of A549 cell viability was due to induction of the cell apoptosis by enhancing the activities of Caspase 3 and Caspase 8. The cell cycle arrest of sub-G1 was found in the cells treated with IndoSN-38 or NaproSN-38. Collectively, these data suggested that the anti-proliferative activities of the NSAID-conjugated SN-38 prodrugs were due to promotion of cell death and arresting the cell cycle which was similar with those of SN-38.

Activity in primate visual cortex is minimally driven by spontaneous movements.

Organisms process sensory information in the context of their own moving bodies, an idea referred to as embodiment. This idea is important for developmental neuroscience, robotics and systems neuroscience. The mechanisms supporting embodiment are unknown, but a manifestation could be the observation in mice of brain-wide neuromodulation, including in the primary visual cortex, driven by task-irrelevant spontaneous body movements. We tested this hypothesis in macaque monkeys (Macaca mulatta), a primate model for human vision, by simultaneously recording visual cortex activity and facial and body movements. We also sought a direct comparison using an analogous approach to those used in mouse studies. Here we found that activity in the primate visual cortex (V1, V2 and V3/V3A) was associated with the animals' own movements, but this modulation was largely explained by the impact of the movements on the retinal image, that is, by changes in visual input. These results indicate that visual cortex in primates is minimally driven by spontaneous movements and may reflect species-specific sensorimotor strategies.

Potential confounds in estimating trial-to-trial correlations between neuronal response and behavior using choice probabilities.

Correlations between trial-to-trial fluctuations in the responses of individual sensory neurons and perceptual reports, commonly quantified with choice probability (CP), have been widely used as an important tool for assessing the contributions of neurons to behavior. These correlations are usually weak and often require a large number of trials for a reliable estimate. Therefore, working with measures such as CP warrants care in data analysis as well as rigorous controls during data collection. Here we identify potential confounds that can arise in data analysis and lead to biased estimates of CP, and suggest methods to avoid the bias. In particular, we show that the common practice of combining neuronal responses across different stimulus conditions with z-score normalization can result in an underestimation of CP when the ratio of the numbers of trials for the two behavioral response categories differs across the stimulus conditions. We also discuss the effects of using variable time intervals for quantifying neuronal response on CP measurements. Finally, we demonstrate that serious artifacts can arise in reaction time tasks that use varying measurement intervals if the mean neuronal response and mean behavioral performance vary over time within trials. To emphasize the importance of addressing these concerns in neurophysiological data, we present a set of data collected from V1 cells in macaque monkeys while the animals performed a detection task.

Synergistic Effect of HAD-B1 and Afatinib Against Gefitinib Resistance of Non-Small Cell Lung Cancer.

In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease progression. Strategies to overcome the resistance are required in treatment for advanced lung cancer. In this study, we investigated the therapeutic effect of afatinib and HangAmDan-B1 (HAD-B1) co-administration in gefitinib-resistant NSCLC using HCC827-GR, NSCLC cell line with gefitinib resistance, and the HCC827-GR cell implanted mouse model. HAD-B1 consists of 4 herbs, Panax notoginseng Radix, Cordyceps militaris, Panax ginseng C. A. Mey, and Boswellia carteri Birdwood, and has been reported to be effective in patients with advanced lung cancer in clinical practice. Our findings demonstrated that HAD-B1 combined with afatinib markedly inhibited cell proliferation and induced apoptosis compared to afatinib monotherapy and HAD-B1 monotherapy. Inhibition of HCC827-GR cell proliferation by HAD-B1 occurred through MET amplification and reduced phosphorylation, and the synergistic effect of afatinib and HAD-B1 induced cell cycle arrest and apoptosis in HCC827-GR cells via the downregulation of ERK and mTOR signaling pathways. In hematology and biochemistry tests, HAD-B1 alleviated the toxicity of tumor. In conclusion, HAD-B1 combined with afatinib would be a promising therapeutic strategy for NSCLC with EGFR-TKI resistance.

Qualitative Analysis of Proteins in Two Snake Venoms, Gloydius Blomhoffii and Agkistrodon Acutus.

Objectives: Snake venom is a complex mixture of various pharmacologically active substances, such as small proteins, peptides, and organic and mineral components. This paper aims to identify and analyse the proteins in common venomous snakes, such as Gloydius blomhoffii (G. blomhoffii) and Agkistrodon acutus (A. acutus), in Korea. Methods: We used mass spectrometry, electrophoresis, N-terminal sequencing and in-gel digestion to analyse the proteins in these two snake venoms. Results: We identified eight proteins in G. blomhoffii venom and four proteins in A. acutus venom. The proteins detected in G. blomhoffii and A. acutus venoms were phospholipase A2, snake venom metalloproteinase and cysteine-rich secretory protein. Snake C-type lectin (snaclec) was unique to A. acutus venom. Conclusion: These data will contribute to the current knowledge of proteins present in the venoms of viper snakes and provide useful information for investigating their therapeutic potential.

Effect of Modified Yukmijihwang-Tang on Sleep Quality in the Rat.

Many plants have been used in Korean medicine for treating insomnia. However, scientific evidence for their sedative activity has not been fully investigated. Thus, this study was carried out to investigate the sedative effects of the extracts of medicinal plants, including Yukmijihwang-tang and its various modified forms through the 5-HT2c receptor binding assay, and to further confirm its sleep-promoting effects and the underlying neural mechanism in rats utilizing electroencephalography (EEG) analysis. Enzyme-linked immunosorbent assay (ELISA) was used to measure serotonin (5-HT) in the brain. The water extracts of modified Yukmijihwang-tang (YmP) displayed binding affinity to the 5-HT2C receptor (IC50 value of 199.9 µg/mL). YmP (50 mg/kg) administration decreased wake time and increased REM and NREM sleep based on EEG data in rats. Additionally, treatment with YmP significantly increased the 5-HT level in the hypothalamus. In conclusion, the sedative effect of YmP can be attributed to the activation of the central serotonergic systems, as evidenced by the high affinity of binding of the 5-HT2C receptor and increased 5-HT levels in the brain of the rat. This study suggests that YmP can be a new material as a sleep inducer in natural products.

Evaluation of Moon-tang on allergic reactions.

Moon-tang (M-tang) is a traditional Korean medicine that has been used for the treatment of various allergic disorders. However, the precise antiallergic effect and mechanism of it remain unknown. To figure out accurately the effect of M-tang on mast cell-mediated allergic reactions, we measured parameters including changes in the compound 48/80-induced systemic anaphylaxis, ear-swelling response, histamine release, passive cutaneous anaphylaxis (PCA), and tumor necrosis factor (TNF)-α secretion and expression, which related to allergic inflammatory reaction. The oral administration of M-tang inhibited systemic anaphylaxis and ear-swelling response in mice. M-tang suppressed the PCA and histamine release. In addition, M-tang and its active component, ß-eudesmol, inhibited the TNF-α production and expression in activated mast cells. These results suggest that M-tang may be a beneficial applicability as a candidate for an antiallergic agent.

Anti-angiogenic effects of water extract of a formula consisting of Pulsatilla koreana, Panax ginseng and Glycyrrhiza uralensis.

OBJECTIVE: This study aimed to investigate the anti-angiogenic effects of the water extract of Pulsatilla koreana (Yabe ex Nakai) Nakai ex T. Mori., Panax ginseng C.A. Meyer and Glycyrrhiza uralensis Fisch (WEPPG). METHODS: The effects of WEPPG on fibroblast growth factor (bFGF)-induced angiogenesis were evaluated by human umbilical vein endothelial cell (HUVEC) proliferation, adhesion, and migration assays. Capillary tube formation of HUVECs and bFGF-induced chick chorioallantoic membrane (CAM) angiogenesis were also observed. WEPPG was used to treat the HUVECs and CAMs, and then various activities such as proliferation, adhesion, migration, capillary tube formation and cell cycle proteins were analyzed. RESULTS: WEPPG significantly inhibited bFGF-induced HUVEC proliferation, adhesion, migration, and capillary tube formation. Signaling protein analysis showed up-regulated expressions of various proteins including cyclin A, p63 and KIP2 and down-regulated expressions of nibrin and focal adhesion kinase. The blood vessel formation in a CAM treated with WEPPG was markedly reduced compared with the control group. CONCLUSION: These results suggested that the inhibition of angiogenesis by WEPPG can be an action mechanism for its anti-cancer effects.

Site-specific inhibition of integrin alpha v beta 3-vitronectin association by a ser-asp-val sequence through an Arg-Gly-Asp-binding site of the integrin.

A functional proteomic technology using protein chip and molecular simulation was used to demonstrate a novel biomolecular interaction between P11, a peptide containing the Ser-Asp-Val (SDV) sequence and integrin alpha v beta 3. P11 (HSDVHK) is a novel antagonistic peptide of integrin alpha v beta 3 screened from hexapeptide library through protein chip system. An in silico docking study and competitive protein chip assay revealed that the SDV sequence of P11 is able to create a stable inhibitory complex onto the vitronectin-binding site of integrin alpha v beta 3. The Arg-Gly-Asp (RGD)-binding site recognition by P11 was site specific because the P11 was inactive for the complex formation of a denatured form of integrin-vitronectin. P11 showed a strong antagonism against alpha v beta 3-GRGDSP interaction with an IC(50) value of 25.72+/-3.34 nM, whereas the value of GRGDSP peptide was 1968.73+/-444.32 nM. The binding-free energies calculated from the docking simulations for each P11 and RGD peptide were -3.99 and -3.10 kcal/mol, respectively. The free energy difference between P11 and RGD corresponds to approximately a 4.5-fold lower K(i) value for the P11 than the RGD peptide. The binding orientation of the docked P11 was similar to the crystal structure of the RGD in alpha v beta 3. The analyzed docked poses suggest that a divalent metal-ion coordination was a common driving force for the formation of both SDV/alpha v beta 3 and RGD/alpha v beta 3 complexes. This is the first report on the specific recognition of the RGD-binding site of alpha v beta 3 by a non-RGD containing peptide using a computer-assisted proteomic approach.

Libanoridin inhibits the mast cell-mediated allergic inflammatory reaction.

BACKGROUND AND AIM: Corydalis heterocarpa is a biennial herb in South Korea, with spikes of yellow flowers. It has been used for as a folk medicine to cure travail and spasm. However, studies on this herb and its secondary metabolites have rarely been reported. In the present study, we isolated secondary metabolite libanlibanoridin from Corydalis heterocarpa. We have also examined the effect of libanoridin on the inflammatory cytokines production in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore, A2318 stimulated human mast cell line, HMC-1. PMA plus A23187 significantly increased interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha production compared to media control (P < 0.05). RESULTS: We report that treatment with libanlibanoridin can inhibit PMA plus A23187-induced IL-1beta, IL-6, IL-8, and TNF-alpha production in a concentration-dependent manner with IC50 of 0.002, 1.38, 1.48, and 0.36 mug/ml, respectively. Maximal inhibition rates of IL-1beta, IL-6, IL-8, and TNF-alpha production by libanlibanoridin were about 117.5%, 86.22%, 86.41%, and 90.74%, respectively. libanoridin inhibits the mRNA expression of IL-1beta, IL-6, IL-8, and TNF-alpha. libanoridin also inhibits the expression of cyclooxygenase-2. CONCLUSION: These results indicate that libanlibanoridin may be helpful in regulating mast cell-mediated allergic inflammatory response.

Protein chip analysis of pluripotency-associated proteins in NIH3T3 fibroblast.

Specific transcription factors regulate the totipotent and pluripotent capability of embryonic stem cells. Amongst these regulatory transcription factors in embryonic stem cells, Oct4 and Nanog are master factors that also have unique characteristic ability of cell-specific pluripotency and self-renewal. The expression of Nanog in fibroblasts confirms increased cell proliferation and transformation of foci-forming phenotype indicative of its oncogenic potential. The expression of Oct4, interestingly, leads to transformation of non-tumorgenic mouse into tumorigenic mouse. Our current investigation ascertains that the resultant increase in DNA synthesis and cell proliferation is the consequence of transforming the phenotype into foci formation. We used a manually curetted ProteoChip to carry out the signaling protein microarray analysis, which revealed up-regulated expression of various proteins including FAK1, MEK1 and Raf1. Some of the proteins explain the mechanism by which Oct4 and Nanog transform the phenotype. In NIH3T3 cells expressed with mouse Oct4 (mOct4), mouse Nanog (mNanog) separately as well as together, the specific knockdown of mFAK1 inhibited morphological transformation of the cells, and their invasion activity. The mFAK1 overexpression leads to morphological transformation as shown with mOct4 and mNanog. Additionally, we showed that the ERK1/2 pathway is involved in the up-regulation of c-myc and cyclin D1 expression mediated by mFAK1. Our results signify that the combinatorial signaling protein-array using biomolecular approach may possibly provide us with a new tool to understand cellular homeostasis.

Erkitinib, a novel EGFR tyrosine kinase inhibitor screened using a ProteoChip system from a phytochemical library.

Receptor tyrosine kinases (PTKs) play key roles in the pathogenesis of numerous human diseases, including cancer. Therefore PTK inhibitors are currently under intensive investigation as potential drug candidates. Herein, we report on a ProteoChip-based screening of an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor, Erkitinibs, from phytochemical libraries. PLC-gamma-1 was used as a substrate immobilized on a ProteoChip and incubated with an EGFR kinase to phosphorylate tyrosine residues of the substrate, followed by a fluorescence detection of the substrate recognized by a phospho-specific monoclonal antibody. Erkitinibs inhibited HeLa cell proliferation in a dose-dependent manner. In conclusion, these data suggest that Erkitinibs can be a specific inhibitor of an EGFR kinase and can be further developed as a potent anti-tumor agent.

The Extract of Cordyceps Militaris Inhibited the Proliferation of Cisplatin-Resistant A549 Lung Cancer Cells by Downregulation of H-Ras.

We investigated the antitumor effect of Cordyceps militaris extract (CME) on A549 cisplatin-resistant (CR) lung cancer cells. The proliferation of A549/CR cells was suppressed by CME. Apoptosis of the cells was induced by CME. The cell cycle arrest was observed in the sub-G1 phase in the cells treated with CME. Proteomic profile analysis showed that H-Ras was downregulated in CME-treated cells and it was confirmed by western blot analysis. Collectively, these data demonstrated that CME is an alternative treatment for the anticancer effect.

Corrigendum to "Antidepressant Effect of Fraxinus rhynchophylla Hance Extract in a Mouse Model of Chronic Stress-Induced Depression".

[This corrects the article DOI: 10.1155/2018/8249563.].