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The psychosocial environment is one of the major contributors of social stress. Family members or caregivers who consistently communicate with individuals with brain disorders are considered at risk for physical and mental health deterioration, possibly leading to mental disorders. However, the underlying neural mechanisms of this phenomenon remain poorly understood. To address this, we developed a social stress paradigm in which a mouse model of epilepsy or depression was housed long-term (>4weeks) with normal conspecifics. We characterized the behavioral phenotypes and electrophysiologically investigated the neural activity of conspecific cagemate mice. The cagemates exhibited deficits in behavioral tasks assessing anxiety, locomotion, learning/memory, and depression-like behavior. Furthermore, they showed severe social impairment in social behavioral tasks involving social interaction or aggression. Strikingly, behavioral dysfunction remained in the cagemates 4weeks following co-housing cessation with the mouse models. In an electrophysiological study, the cagemates showed an increased number of spikes in medial prefrontal cortex (mPFC) neurons. Our results demonstrate that conspecifics co-housed with mouse models of brain disorders develop chronic behavioral dysfunctions, and suggest a possible association between abnormal mPFC neural activity and their behavioral pathogenesis. These findings contribute to the understanding of the psychosocial and psychiatric symptoms frequently present in families or caregivers of patients with brain disorders.

Antibody arrays are a useful for detecting antigens and other antibodies. This technique typically requires a uniform and well-defined orientation of antibodies attached to a surface for optimal performance. A uniform orientation can be achieved by modification of antibodies to include a single site for attachment. Thus, uniformly oriented antibody arrays require a bioengineered modification for the antibodies directly immobilization on the solid surface. In this study, we describe a "sandwich-type" antibody array where unmodified antibodies are oriented through binding with regioselectively immobilized recombinant antibody-binding protein L. Recombinant proL-CVIA bearing C-terminal CVIA motif is post-translationally modified with an alkyne group by protein farnesyltransferase (PFTase) at the cysteine residue in the CVIA sequence to give proL-CVIApf, which is covalently attached to an azido-modified glass slide by a Huisgen [3 + 2] cycloaddition reaction. Slides bearing antibodies bound to slides coated with regioselectively immobilized proL-CVIApf gave stronger fluorescence outputs and those where the antibody-binding protein was immobilized in random orientations on an epoxy-modified slide. Properly selected capture and detection antibodies did not cross-react with immobilized proL-CVIApf in sandwich arrays, and the proL-CVIApf slides can be used for multiple cycles of detected over a period of several months.

Immobilized antibodies are useful for the detection of antigens in highly sensitive microarray diagnostic applications. Arrays with the antibodies attached regioselectively in a uniform orientation are typically more sensitive than those with random orientations. Direct regioselective immobilization of antibodies on a solid support typically requires a modified form of the protein. We now report a general approach for the regioselective attachment of antibodies to a surface using truncated forms of antibody-binding proteins A, G, and L that retain the structural motifs required for antibody binding. The recombinant proteins have a C-terminal CVIX protein farnesyltransferase recognition motif that allows us to append a bioorthogonal azide or alkyne moiety and use the Cu(I)-catalyzed Huisgen cycloaddition to attach the binding proteins to a suitably modified glass surface. This approach offers several advantages. The recombinant antibody-binding proteins are produced in Escherichia coli, chemoselectively modified posttranslationally in the cell-free homogenate, and directly attached to the glass surface without the need for purification at any stage of the process. Complexes between immobilized recombinant proteins A, G, and L and their respective strongly bound antibodies were stable to repeated washing with PBST buffer at pH 7.2. However, the antibodies could be stripped from the slides by treatment with 0.1 M glycine·HCl buffer, pH 2.6, for 30 min and regenerated by shaking with PBS buffer, pH 7.2, at 4 °C overnight. The recombinant forms of proteins A, G, and L can be used separately or in combination to give glass surfaces capable of binding a wide variety of antibodies.

Center for Drug Discovery Platform Technology, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea Received November 1, 2011, Accepted November 11, 2011We report the solid-phase library construction of 222 number of a novel N-[alkyl sulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 1A and amine 1B derivatives. The polymer-bound N-[alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 9 and amine 10 derivativeswere obtained by first diversity generation with various acid chlorides and alkyl halides. Further reactions onthe resins 9 and 10 with substituted sulfonyl chlorides produced the desired N-[alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 1A and amine 1B analogues.Key Words : Spiro(2H-1-benzopyran-2,4-piperidine)-6-yl derivatives, Solid-phase parallel synthesis, Drug-like benzopyran core skeleton IntroductionHeterocyclic compounds provide scaffolds on whichpharmacophores can be arranged to yield potent andselective drugs, and a variety of heterocycles have beensynthesized on solid support.

This paper presents an electrical power monitoring system for home energy management and an automatic appliance-identification algorithm based on the electricity-usage patterns collected during the monitoring tests. This paper also discusses the results of the field tests of which the proposed system was voluntarily deployed at 13 homes. The proposed monitoring system periodically measures the amount of power consumption of each appliance with a pre-specified time interval and effectively displays the essential information provided by the monitored data which is required users to know in order to save power consumption. Regarding the field tests of the monitoring system, the households responded that the system was useful in saving electricity and especially the electricity-usage patterns per appliances. They also considered that the predicted amount of the monthly power consumption was effective. The proposed appliance-identification algorithm uses 4 patterns: Zero-Crossing Rate(ZC), Variation of On State(VO), Slope of On State(SO) and Duty Cycle(DC), which are applied over the 2 hour interval with 25% of it on state, and it yielded 82.1% of success rate in identifying 5 kinds of appliances: refrigerator, TV, electric rice-cooker, kimchi-refrigerator and washing machine.

Summary Purpose: Stem cell–based therapies are being considered for various neurologic diseases, such as epilepsy. Recent studies have suggested that some effects of transplanted stem cells are due to bystander effects that modulate the host environment, rather than direct effects of cell replacement. The extract from human adipose stem cells (ASCs) that secrete multiple growth factors including cytokines and chemokines may be a potential source of bystander effects for the treatment of epilepsy, in which inflammation is thought to play an important role. Here, we investigated the effects of a cytosolic extract of human ASCs (ASCs-E) in a mouse model of epilepsy. Methods: Human ASCs-E, boiled ASCs-E, or fibroblast-extract (fibroblast-E) was intraperitoneally administrated to C57BL/6 mice 15 min before pilocarpine-induced status epilepticus (SE) or during chronic epileptic stage. Blood–brain barrier (BBB) leakage was evaluated by measuring Evans blue dye extravasation. Spontaneous recurrent seizure (SRS) was investigated by long-term video–electroencephalography (EEG) monitoring. The mice performed elevated plus maze, open-field, light/dark transition, and novel object recognition tasks. Key Findings: Acute application of human ASCs-E before SE led to earlier attenuation of seizure spike activities after treatment with diazepam, reduction of BBB leakage, and inhibition of the development of epilepsy. Human ASCs-E treatment (for 7 days) during the chronic epileptic stage suppressed SRS and reduced abnormal epileptic behavioral phenotypes. However, neither boiled ASCs-E nor fibroblast-E had any effects in the experimental epilepsy model. Significance: Our results demonstrate that human ASCs-E prevents or inhibits epileptogenesis and SRS in mice. They also suggest a stem cell–based, noninvasive therapy for the treatment of epilepsy.

Department of Chemistry, Faculty of Science, Gakushuin University, Tokyo 171-8588, JapanReceived October 8, 2010, Accepted April 28, 2011Key Words : Boron neutron capture therapy (BNCT), ortho-carborane, 4-Aminobenzoic acid, 4-Hydroxyben-zoic acid, Glutamic acidBoron neutron capture therapy (BNCT) has recentlyreceived considerable attention due to a highly selectivetherapy for treating cancer in clinical trial.

A general method developed for the parallel solid-phase synthesis of sn-1,2- and sn-2,3-diacyglycerol derivatives. The technique relies on the use of carboxylic acid-promoted epoxide ring-opening reactions of the glycidyl-bound resin 3. The polymer-bound monoacylglycerol 5, formed in this manner, is transformed to the respective polymer-bound diacylglycerols 7 and 9 by reaction of the free alcohol moiety with a second carboxylic acid under conditions that lead to retention or inversion of C-2 stereochemistry. The sequence is completed by BCl3-promoted cleavage of 7 and 9 to form the sn-1,2- and sn-2,3-diacylglycerols, respectively.

2,2-Dimethyl-3,4-dialkoxy-substituted 6-aminobenzopyran analogues (eg., 7 and 8) were identified as prolyl 4-hydroxylase inhibitors via a screening process using HSC-T6 and LI 90 cells that express an immortalized rat hepatic stellate cell line and as part of a test of the type I collagen contents employing the ELISA method. A subsequent lead optimization effort based on solid-phase parallel synthesis led to the identification of 2,2-dimethyl-3,4-dialkoxy-substituted 6-aminobenzopyrans as potent inhibitors of prolyl 4-hydroxylase.

The reaction of Cu(NO 3 ) 2 containing NH 4 PF 6 with btp ligands produced a new polymeric compound 1 containing Cu ( H 2 O ) 2 2 + and Cu(NO 3 ) 2 units alternatively bridged by btp ligands with H-bonds between copper-bonded water and nitrate oxygen atoms. Crystal Data: M =1465.97, space group P2/n , a =11.6300(3) A, b =12.8000(4) A, c =19.2960(6) A, β =98.6200(19)°, V =2840.03(15) A 3 , Z =2, μ =0.926 mm −1 , Dc =1.714 Mg/m 3 , R =0.0629, wR =0.1614. The polymeric compound 1 has shown the heterogeneous catalytic activity for the ring opening of epoxides under mild conditions. This catalyst system appears to be an efficient, mild, and easily recyclable method for the alcoholysis of epoxides. In addition, the heterogeneous catalyst 1 has, surprisingly, shown even better catalytic activity than copper salt system in homogeneous condition.

A general method is reported for the parallel solid-phase synthesis of hydroxypiperazine derivatives based on the oxidation–Cope elimination of polymer-bound phenethylamine linker with m -CPBA. The key intermediate of phenethylamine N -oxide resins was separable on solid-phase for subsequent β-elimination, from which the desired hydroxypiperazine products could be obtained in high purities and yields without any significant contamination at 90 °C for 2 h. The utility of the methodology for solid-phase synthesis of general hydroxylamines was also investigated using the same linker. The progress of reactions could be monitored on polymer bound intermediates by ATR-FTIR spectroscopy on single bead. The desired products were obtained in good six-step overall yields upon cleavage from the resins and were characterized by LC/MS, 1 H NMR, and 13 C NMR spectroscopy.

with boronic acids or other organoboranes. These methods are mild, efficient, and regioselective. However, there are several limitations of these methods. The acid derivatives are not commercially available and anhydride is inefficient to use because the half part of car-boxylic anhydride is lost as a leaving group. Goosen and his coworkers reported a palladium-catalyzed synthesis of aryl ketones directly by the reaction of boronic acids with active ester or anhydride of carboxylic acid generated

A new vinyl ether type of linker based on 4-hydroxy phenethyl alcohol is developed for the solid-phase synthesis as demonstrated in the Suzuki type of aryl–aryl coupling reaction for the preparation of various biphenyl tetrazole derivatives.

There is even more interest in the development of the solid-phase synthetic approaches to small molecules, particularly those which embrace heteroatom-containing molecules, for the purpose of medicinal and agricultural chemistry.1 Many heteroatom-containing molecules exhibit a broad range of biological activities for antiviral, antibacterial, antifungal, and antihypertensive drugs, as well as others.2 The major impediment in the solid-phase synthesis is the lack of analytical techniques for identifying the products and particularly for monitoring the progress of the reactions. As part of our continuing interest in the development of new solid-phase synthetic methods,3 we were looking for a new analytical method for monitoring the reaction and for identifying the product still bound to the polymer. Although there are a few techniques known for direct monitoring of samples still bound to resins, namely IR,4 NMR,5 and mass spectroscopy,6 we still need a new analytical method.7 X-ray photoelectron spectroscopy (XPS) has been widely used to acquire qualitative as well as detailed quantitative information about the composition and structure of organic and polymeric materials.8 As an analytical tool for organic and polymeric materials, XPS is known to have several advantages: It is a semiquantitative technique with a high surface sensitivity and is capable of identifying all elements except H and He. Also, XPS provides information about chemical states of elements.8 Since the most popular solid supports, such as the Wang and Merrifield resins, are mainly comprised of carbon and oxygen atoms and the concentration of the reacting site is very low (1-2 mmol per gram of resin), a simple XPS analysis of these polymers will only provide a limited piece of information.9 However, we envisioned that if we insert a suitable heteroatom as an internal standard (a marker) in the polymer, then we might be able to monitor around the Figure 1. X-ray photoelectron survey spectra for resins 1, 3, 5, and 6. The elements in the polymer-bound compounds can be readily identified by determining the binding energies of the photoelectron peaks. © Copyright 1999 by the American Chemical Society

Protein chips are powerful tools as analytical and diagnostic devices for detection of biomolecular interactions, where the proteins are covalently or noncovalently attached to biosensing surfaces to capture and detect target molecules or biomarkers. Thus, fabrication of biosensing surfaces for regio- and chemoselective immobilization of biomolecules is a crucial step for better biosensor performance. In our previous studies, a regio- and chemoselective immobilization strategy was demonstrated on glass surfaces. This strategy is now used to regioselectively attach proteins to self-assembled monolayers (SAMs) on gold surfaces. Recombinant green fluorescent protein (GFP), glutathione S-transferase (GST), and antibody-binding protein G, bearing a C-terminal CVIA motif, were prepared and a farnesyl analogue with an ω-alkyne moiety was attached to the sulfhydryl moiety in the cysteine side chain by protein farnesyltransferase. The proteins, modified with the bioorthogonal alkyne functional group, were covalently and regioselectively immobilized on thiol or dithiocarbamate (DTC) SAMs on a gold surface by a Huigsen [3 + 2] cycloaddition reaction with minimal nonspecific binding. A concentration-dependent increase of fluorescence intensity was observed in wells treated with GFP on both thiol- and DTC-SAMs. The highly ordered, densely packed layer allowed for a high loading of immobilized protein, with a concomitant increase in substrate binding capacity. The DTC-SAMs were substantially more resistant to displacement of the immobilized proteins from the gold surface by β-mercaptoethanol than alkane-thiol SAMs.

A dihydropyran carboxylic acid type linker is suitable for the solid phase Suzuki type aryl-aryl coupling reaction for the preparation of various biphenyltetrazole derivatives.

Atypical absence epilepsy (AAE) showing slow spike-and-wave discharges (SWD) is characterized by severely abnormal cognition and neurodevelopmental or neurological outcomes in humans. However, despite the severe behavioral outcomes in AAE, the relationship between AAE and social-behavioral dysfunctions has not defined well, either experimentally or in patients with AAE. Experimentally, AAE can be produced by administering AY-9944 (AY), a cholesterol biosynthesis inhibitor. In this study, we characterized social behavior in the AY mouse model of AAE. AAE in the mouse was induced by repeated postnatal administration of AY every 6 days from postnatal day (P) 2 to P20. AY-treated mice exhibited spontaneous, recurrent, and synchronous SWD (4-5 Hz) in electroencephalographic recordings. AY-treated mice performed tasks involving sociability/social novelty preference, social interaction with a juvenile conspecific, observational fear, and resident-intruder aggression. They showed behavioral dysfunction in social interactions with a juvenile conspecific and sociability/social novelty preference tasks. They also exhibited reduced social fear learning in observational fear conditioning. Interestingly, they showed increased levels of offensive behaviors in a resident-intruder task. However, AY-treated mice displayed normal levels of anxiety in light/dark transition and the elevated plus maze tasks, and showed slightly increased locomotor activity in an open-field task. These results demonstrate social dysfunction in the AY-induced AAE model. Our study of social behavior can also provide valuable information about Lennox-Gastaut syndrome, in which AAE is a component. Thus, our findings may help to understand behavioral pathogenesis or characteristics of patients with AAE.

Many patients with epilepsy are afflicted with psychiatric comorbidities including social dysfunction. However, although social deficits have been a major concern in epilepsy treatment, the relationship between social behavioral pathogenesis and the time course of epileptogenesis is not well defined. To address this, we investigated social behavioral alterations and cortical rhythms during two distinct periods in a mouse model of temporal lobe epilepsy (TLE): 1) a seizure-free, latent period after status epilepticus and 2) the subsequent, chronic period characterized by spontaneous recurrent seizures (SRSs). We found that severe social impairments, such as reduced sociability/social novelty preference, social interaction, social learning, and enhanced defensiveness, appeared during the latent period in mice with TLE. The social dysfunctions in the latent-period mice were nearly comparable to those in the chronic-period mice. We also found that both the latent- and chronic-period mice showed similar aberrant neural activities. They showed enhanced delta-band (1–4 Hz) activity and reduced alpha- (8.5–12 Hz) and gamma-band (30–55 Hz) activity during baseline behavior. Interestingly, concomitant increases in alpha- and gamma-band activities during social behavior, which were characteristic in control mice, were not observed in either latent- or chronic-period mice. Our results indicate that social deficits and abnormal neural activities appear at an earlier stage in epileptogenesis regardless of SRS occurrence. These findings may help to understand behavioral pathogenesis in patients with TLE and at-risk patients with initial insults that develop into TLE.

Stem cell-based therapies are being considered for various neurologic diseases, such as epilepsy. Recent studies have suggested that some effects of transplanted stem cells are due to bystander effects that modulate the host environment, rather than direct effects of cell replacement. The extract from human adipose stem cells (ASCs) that secrete multiple growth factors including cytokines and chemokines may be a potential source of bystander effects for the treatment of epilepsy, in which inflammation is thought to play an important role. Here, we investigated the effects of a cytosolic extract of human ASCs (ASCs-E) in a mouse model of epilepsy.Human ASCs-E, boiled ASCs-E, or fibroblast-extract (fibroblast-E) was intraperitoneally administrated to C57BL/6 mice 15 min before pilocarpine-induced status epilepticus (SE) or during chronic epileptic stage. Blood-brain barrier (BBB) leakage was evaluated by measuring Evans blue dye extravasation. Spontaneous recurrent seizure (SRS) was investigated by long-term video-electroencephalography (EEG) monitoring. The mice performed elevated plus maze, open-field, light/dark transition, and novel object recognition tasks.Acute application of human ASCs-E before SE led to earlier attenuation of seizure spike activities after treatment with diazepam, reduction of BBB leakage, and inhibition of the development of epilepsy. Human ASCs-E treatment (for 7 days) during the chronic epileptic stage suppressed SRS and reduced abnormal epileptic behavioral phenotypes. However, neither boiled ASCs-E nor fibroblast-E had any effects in the experimental epilepsy model.Our results demonstrate that human ASCs-E prevents or inhibits epileptogenesis and SRS in mice. They also suggest a stem cell-based, noninvasive therapy for the treatment of epilepsy.

with boronic acids or other organoboranes. These methods are mild, efficient, and regioselective. However, there are several limitations of these methods. The acid derivatives are not commercially available and anhydride is inefficient to use because the half part of car-boxylic anhydride is lost as a leaving group. Goosen and his coworkers reported a palladium-catalyzed synthesis of aryl ketones directly by the reaction of boronic acids with active ester or anhydride of carboxylic acid generated

From a screen of small molecule libraries to identify potential therapeutics for psychostimulant abuse, 3-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-ones were shown to be isoform-selective PKC-zeta inhibitors.

A 2000-member library of benzopyran analogues was prepared by using a solid-phase synthesis protocol. Polymer-bound 6-alkylaminobenzopyrans 7 were synthesized as part of a first generation diversification step by employing reactions of a variety of alkyl halides with the amine 6. Transformations of the resin-bound intermediates 8 formed in this manner by reactions with acid halides, sulfonyl chlorides, and isocyanates leads to introduction of the second level of diversification found in the series of 6-alkylamino-2-(functionalized-aminomethyl)-2-methyl-2H-1-benzopyran analogues 11 and 12.

[reaction: see text] A library containing 1200 analogues of 2,6-difunctionalized 2-methyl-2H-1-benzopyran was constructed by using a solid-phase synthesis protocol. Polymer-bound 6-amido-, 6-sulfonamido-, and 6-uredo-functionalized 2-hydroxymethyl-2-methylbenzopyrans 10 were prepared as part of a first-generation diversification step by employing reactions of respective acid halides, sulfonyl chlorides, and isocyanates with the amine precursor 7. Transformations of the resin-bound intermediates 10 by reactions with alkyl and acid halides were then used to produce a diverse series of 2,6-difunctionalized 2-methyl-2H-1-benzopyran analogues 12 and 14.

We report the solid-phase library construction of 2000 analogues of 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran. The polymer-bound hydroxyalkoxychromanes 5, produced by nucleophilic reactions with various alcohols on epoxides generated in situ, served as key intermediates for subsequent diversification. Further reactions on these hydroxyalkoxychromanes 5 with various electrophiles, such as alkyl halides and acid halides, produced the desired 6-amino-2,2-dimethyl-3,4,6-trisubstituted-2H-1-benzopyran analogues 9, 10, and 11. The progress of reactions could be monitored as solid-bound intermediates by ATR-FTIR or HR-MAS-NMR spectroscopy. The final compounds, obtained in good yields and high purity upon cleavage from the resins, were characterized by LC/MS, HRMS, (1)H NMR, and (13)C NMR spectroscopy.

The structure of the tetradentate Co(III) complex was determined by the X-ray diffraction method. Four N atoms of the 1,2-bis(2-pyridine-2-carboxamido)benzene (bpb2-) ligand and two chloro ligands are coordinated to the Co(III) atom with a Cl-Co-Cl angle of 176.18(7)°. The coordination geometry of the Co atom is distorted octahedral(Oh).

The structure of the title compound, [Mn(TPP)(t-BuOH)2][ClO4], has been determined by an X-ray diffraction method. Four N atoms of the porphyrin and two tert-butanols are coordinated to the Mn(III) ion. Long Mn-O(axial) distances of 2.299(4) and 2.287(4)A and typical Mn-N(equatorial) distances of 1.988(4) - 1.995(4)A lead to a tetragonal distortion. The O1-Mn-O2 bond angle is 175.06(14)°.

The N4 donor ligand, Me2bpzb2− and a pyridine molecule are coordinated to the Zinc(II) so that the coordination geometry closely resembles a square-pyramidal environment with a nitrogen atom of the pyridine ligand occupying the apical position. Copyright © 2003 John Wiley & Sons, Ltd.

A zinc(II) coordination polymer has been formed from Zn(NO3)2 and 2,6-bis(N′-1,2,4-triazolyl)pyridine (btp) ligands in which each zinc(II) atom is coordinated by three nitrogen donor atoms from btp and three oxygen donor atoms from a nitrate and two water molecules. Copyright © 2003 John Wiley & Sons, Ltd.

The systematic oxidation reactions of a wide range of alcohols have been carried out by using an iron porphyrin complex in order to understand their relation to cytochrome P-450 enzymes and to have a practical application to organic synthesis. The iron porphyrin complex catalyzed efficiently alcohol oxidation to the respective carbonyl compound via a high-valent iron-oxo porphyrin intermediate ((Porp)Fe=O+). Several mechanistic studies such as isotope 18O labeling, deuterium isotope effect, linear free energy relationship, and ring-opening of radical clock substrate, have suggested that the alcohol is oxidized by a sequence of reactions involving an alpha-hydroxyalkyl radical intermediate and oxygen rebound to form the gem-diol, dehydration of which yields the carbonyl compounds. Moreover, it has been proposed that a two-state reactivity mechanism can also be adopted for alcohol oxidation reactions in iron porphyrin model systems as exhibited by P-450 enzymes.