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Background There is emerging evidence for abnormal beta oscillations in psychosis. Beta oscillations are likely to play a key role in the coordination of sensorimotor information that is crucial to healthy mental function. Growing evidence suggests that beta oscillations typically manifest as transient beta bursts that increase in probability following a motor response, observable as post-movement beta rebound. Evidence indicates that post-movement beta rebound is attenuated in psychosis, with greater attenuation associated with greater symptom severity and impairment. Delineating the functional role of beta bursts therefore may be key to understanding the mechanisms underlying persistent psychotic illness. Methods We used concurrent electroencephalography and functional magnetic resonance imaging to identify blood oxygen level–dependent correlates of beta bursts during the n-back working memory task and intervening rest periods in healthy control participants (n = 30) and patients with psychosis (n = 48). Results During both task blocks and intervening rest periods, beta bursts phasically activated regions implicated in task-relevant content while suppressing currently tonically active regions. Patients showed attenuated post-movement beta rebound that was associated with persisting disorganization symptoms as well as impairments in cognition and role function. Patients also showed greater task-related reductions in overall beta burst rate and showed greater, more extensive, beta burst–related blood oxygen level–dependent activation. Conclusions Our evidence supports a model in which beta bursts reactivate latently maintained sensorimotor information and are dysregulated and inefficient in psychosis. We propose that abnormalities in the mechanisms by which beta bursts coordinate reactivation of contextually appropriate content can manifest as disorganization, working memory deficits, and inaccurate forward models and may underlie a core deficit associated with persisting symptoms and impairment.

In this study, we attempted to carry out the Mitsunobu 1,4-elimination using the kojic acid analog 3, which carries a hydroxymethyl group on C-6 introduced by aldol condensation, to obtain an effective Michael acceptor 4. To the ethyl acetate solution of 3 and Ph3P, diisopropyl azodicarboxylate was added quickly at 0 °C, resulting in the immediate generation of a yellow precipitate. NMR, mass spectrometry, and X-ray crystal structure analyses allowed to identify the precipitate as a diastereomeric/racemic mixture of dimeric compounds of 4. The dimerization reaction was hypothesized to occur through two major steps: (i) intramolecular dehydration of 3 by Mitsunobu reagents and (ii) homocoupling of the dehydration product 4 to form a new trans-carbon–carbon double bond. Presumably, the enol ether moiety of 4 acts as an electron donor and immediately attacks the α,β-unsaturated carbonyl group of another molecule via a reaction that can be dubbed “Mitsunobu homocoupling.”

In this study, we improved the method for the isolation and purification of the bioactive compound shikonin from the dried root of the traditional Chinese medicinal plant Lithospermum erythrorhizon without a tedious chromatographic separation. Furthermore, we also attempted the solubilization of shikonin in water with cyclodextrins (CDs) using a solid phase “high-speed vibration milling”. Among the various CDs, sulfobutylether-β-CD (SBEβ-CD) showed a highest solubilizing ability and 52.5% of shikonin was solubilized with equimolar amount of SBEβ-CD. In addition, the SBEβ-CD·shikonin complex showed higher apoptogenic activity than that of the same concentration of free shikonin against murine primary peritoneal macrophages. These results indicate that SBEβ-CD is a suitable excipient for clinical application of shikonin.

Purpose Sustained hepatic inflammation derived from parenchymal liver injury is a major driving force of fibrogenesis. We synthesized S-allyl-glutathione (SAG) which regulates macrophage (MO) polarization, and investigated whether SAG can improve liver fibrosis. Method Liver fibrosis was induced by CCl4 injection twice a week for 9 weeks in rats. SAG was administered as a mixed diet from the starting CCl4. To study fibrosis regression, rats were orally administered SAG for 5 weeks after terminating CCl4. In vitro studies were performed effects of SAG (10 -14M~) on M1 or M2 polarization of isolated Kupffer cells (KCs) or bone marrow derived MO (BMDM), and its interactions with isolated hepatic stellate cells (HSCs). Result and Discussion SAG markedly inhibited liver fibrogenesis in a dose-dependent manner and various fibrosis markers. In the fibrolysis stage, SAG accelerated fibrolysis after development of liver chirrosis and decreased the amount of M2 MO. Both Col1A1 and HSP47 mRNA in day 6 HSCs were inhibited by the conditioned medium of SAG-treated MO with M2 inducers onto day 3 HSCs. SAG did not directly inhibit HSC activation. In the M1 MO, SAG also inhibited. These findings suggested that SAG could improve liver cirrhosis via the attenuation of excess polarization in KCs.

In a previous study, we showed that (1′S)-acetoxychavicol acetate ((S)-ACA) caused a rapid decrease in glutathione (GSH) levels less than 15 min after exposure. (S)-ACA-induced cell death was reversed by the addition of N-acetylcysteine. In the current study, we investigated the inhibitory activities of 13 derivatives of (S)-ACA on tumor cell viability, intracellular GSH level and GR activity. Correlations were found among a decrease in cell viability, intracellular GSH levels and the activity of GR in Ehrlich ascites tumor cells treated with the various ACA analogues. A test of the 13 derivatives revealed that the structural factors regulating activity were as follows: (1) the para or 1′-position of acetoxyl group (or other acyl group) was essential, (2) the presence of a C2′–C3′ double or triple bond was essential, and (3) the S configuration of the 1′-acetoxyl group was preferable.

A new multifunctional gene delivery system was constructed with diphtheria toxin's functional domains. Used functional domains are T domain for endosomal escape and R domain for efficient internalization into cell. In order to conjugate these domains into PEI polyplex, diphtheria toxin T and R domains-streptavidin fusion protein (DTRS) was prepared. The conjugation of the DTRS with biotinylated PEI polyplex (DTRS-polyplex) lead to the significant enhancement of transfection efficiency when compared with plain PEI/pDNA polyplex in CHO-K1 cell. It was demonstrated that DTRS-polyplex had high endosomal escape efficiency and internalization efficiency by several measurements, such as in vitro intracellular trafficking observation and the internalization inhibition with several inhibitors. These results suggest that this multifunctional non-viral vector may contribute to the future cancer gene therapy.

The endosomal escape is a well-known serious obstacle for non-viral gene delivery. This is because of an acidic and enzymatic degradation of the contents of the endosome/lysosome. Therefore, the internalized gene needs to be efficient released into the cytosol to obtain the efficiently transfection efficiency. On the other hand, the diphtheria toxin T domain fuses with endosome membrane by pH decrease, then enhances the endosomal escape of the diphtheria toxin C fragment. In this study, we constructed diphtheria toxin T domain-conjugated poly(ethylenimine)s (PEI) polyplex for enhancing the endosomal escape of exogenous gene. The conjugation of diphtheria toxin T domain with PEI/pDNA polyplex leads to the significant enhancement of transfection efficiency when compared with plain PEI/pDNA polyplex. The pH-responsive increase in hydrophobicity of the diphtheria toxin T domain might not only trigger the perturbation of the endocytic vesicle membrane but might also increase the membrane permeability.

Elucidation of the mechanisms underlying potential anticancer drugs continues and unraveling these mechanisms would not only provide a conceptual framework for drug design but also promote use of natural products for chemotherapy. The biological effects of (1′S)-acetoxychavicol acetate ((S)-ACA) have been widely investigated. However, in most cases, a natural product or synthetic racemic compound was used in the study. In this study, we prepared (S)-ACA and its enantiomer (R)-ACA by a lipase-catalyzed esterification method and sought to determine the mechanisms of action of (S)-ACA and (R)-ACA in the growth inhibitory effect in Ehrlich ascites tumor cells (EATC). (S)-ACA caused an accumulation of tumor cells in the G1 phase of the cell cycle, which was accompanied by a decrease in phosphorylated retinoblastoma protein (Rb), an increase in Rb and a decrease in the phosphorylation of p27kip1. However, (R)-ACA caused an accumulation of tumor cells in the G2 phase of the cell cycle, an increase in hyperphosphorylated Rb and an increase in the phosphorylation of p27kip1. The results obtained in the present study demonstrate for the first time, to the best of our knowledge, that both (S)-ACA and (R)-ACA caused the inhibition of tumor cells growth but the inhibition was caused via different mechanisms.

The Hamilton Rating Scale for Depression (HAMD) is the de facto international gold standard for the assessment of depression. There are some criticisms, however, especially with regard to its inter-rater reliability, due to the lack of standardized questions or explicit scoring procedures. The GRID-HAMD was developed to provide standardized explicit scoring conventions and a structured interview guide for administration and scoring of the HAMD. We developed the Japanese version of the GRID-HAMD and examined its inter-rater reliability among experienced and inexperienced clinicians (n = 70), how rater characteristics may affect it, and how training can improve it in the course of a model training program using videotaped interviews. The results showed that the inter-rater reliability of the GRID-HAMD total score was excellent to almost perfect and those of most individual items were also satisfactory to excellent, both with experienced and inexperienced raters, and both before and after the training. With its standardized definitions, questions and detailed scoring conventions, the GRID-HAMD appears to be the best achievable set of interview guides for the HAMD and can provide a solid tool for highly reliable assessment of depression severity.

Ceramides act as a second messenger of the apoptotic signaling process. The allylic alcohol portion comprising the C-3, C-4, and C-5 carbons is essential for this function. The suggestion has been made that this alcohol moiety is oxidized in mitochondria to a carbonyl moiety, with the generation of reactive oxygen species. However, there is no established precedent for the apoptotic performance of 3-ketoceramides thus presumed. In this work, we have synthesized three different types of short-chain 3-ketoceramides, that is, (2 S , 4 E )-2-acetylamino-3-oxo-4-octadecen-1-ol ( A ), (2 S , 4 E , 6 E )-2-acetylamino-3-oxo-4,6-octadecadien-1-ol ( B ), and (2 S , 4 E )-2-acetylamino-1-methoxy-3-oxo-4-octadecene ( C ), and demonstrated that these 3-ketoceramides are capable of inducing effective apoptosis in human leukemia HL-60 cells. In particular, the two monoenoic compounds, A and C , are far more powerful than the corresponding alcoholic analogue, N -acetyl- d - erythro -sphingosine. Observations of DNA fragmentation, caspase-3 activation, and cytochrome c release from mitochondria provide substantiated evidence for mitochondrial apoptosis and the effects of exogenous glutathione on these phenomena are also discussed.

(2 R ,3 Z )-, (2 R ,3 E )-, (2 S ,3 Z ) and (2 S ,3 E )-2-Acetylamino-3-octadecen-1-ol, and (2 R )- and (2 S )-2-acetylamino-octadecan-1-ol were prepared using the Wittig olefination of Garner's aldehyde ( N -Boc- N , O -isopropylidene- l - or d -serinal) from l - or d -serine. The apoptotic activities of these saturated and unsaturated 2-acetylaminoalcohols were examined in human leukemia HL-60 cells using MTT assay. Among the newly synthesized compounds, the cis -isomers were the most potent. Despite their simple structures, (2 R ,3Z)- and (2 S ,3 Z )-2-acetylamino-3-octadecen-1-ol showed high and comparable apoptotic activities compared with N -acetyl- d - erythro -sphingosine (D- e -C2-Cer, a well-known inducer of apoptosis). Their apoptotic activities were in the order d - e -C2-Cer≈ l - e -C2-Cer≈(2 R ,3 Z )-≈(2 S ,3 Z )->>(2 R ,3 E )-≈(2 S ,3 E )-≈(2 R )-≈(2 S )-derivative. Qualitative analysis of DNA fragmentation caused by these compounds was conducted using agarose gel electrophoresis, and typical DNA fragmentation was found in the cases of (2 R ,3 Z )- and (2 S ,3 Z )-isomers such as C2-Cer, but not trans and saturated isomers. The morphological features of the cells, the proteolytic processing of pro-caspase-3, and the cleavage of PARP as a result of exogenous treatment with (2 R ,3 Z )- and (2 S ,3 Z )-isomers indicated that cell death induced by these compounds was apoptosis. These observations suggest that these newly synthesized compounds, ( 3Z )-2-Acetylamino-3-octadecen-1-ol, have similar characteristics and apoptosis-inducing activities against HL-60 cells with C2-Cer.

Non-natural ceramide analogues, C2-homo-ceramide and C2-homo-dihydroceramide, were prepared from L-aspartic acid via L-homo-serine. The apoptotic activities of the synthesized ceramide analogues were examined in HL-60 human leukemia cells. C2-homo- and C2-bishomo-ceramide indicate low but considerable apoptotic activities in comparison with C2-ceramide.

Novel and non-natural ceramide analogues, having a different methylene spacer between the primary hydroxymethyl group and aminomethane of sphingosine backbone, have been prepared from l -glutamic acid. The key step in the preparation is the diastereoselective reduction of an enone adjacent to a Boc protected amino group by reducing agents.

A time series analysis of electroconvulsive (ECT) seizures was performed in patients with depression, examining ictal electroencephalography (EEG), electromyography (EMG), and heart rate (HR) over time, particularly with respect to the physiological interrelations of the ECT seizures. A total of 200 seizures from 21 consecutive patients were analyzed. EEG and EMG data were analyzed by discrete Fourier transform-based continuous wavelet analysis using Morlet wavelet. The time to peak value was investigated for each of these physiological measures. The first group of peaks was the EMG power and the first point of peak HR; the second was EEG power and the last point of peak HR; the third was EMG duration; the fourth was EEG duration; and the fifth was the time of the lowest HR. The time to peak in the central EEG power was associated with that in the low frequency EMG power, the time to peak HR and the time to peak in the frontal pole EEG power. The time to peak in the frontal pole EEG power was associated with that in the central EEG power. The central EEG was considered to be more relevant for seizure generalization than the frontal pole EEG.

Ictal heart rate (HR) and postictal suppression in ictal EEG are believed to be predictive of the therapeutic efficacy of eletroconvulsive therapy (ECT) for depression. However, regarding ictal peak HR, previous studies investigated ictal HR on only one or two occasions during the course of ECT. We prospectively examined whether two physiological parameters, ictal peak HR and postictal suppression in ictal EEG, during every session, including those with abortive seizure, predicted ECT efficacy. Ictal peak HR and postictal suppression index were analyzed in 53 consecutive inpatients with depression using generalized estimating equations analysis, which corrects for the repeated nature of the observations. The peak HR and postictal suppression index were associated with therapeutic efficacy in remitters during sessions with adequate seizure. The physiological characteristics of the remitters included lower peak HR, lower stimulus energy, and higher postictal suppression index. However, these results could not be generalized, and are limited to non-atropine conditions and bilateral ECT.

The authors regret that in reference 3 of the above article, the following citation was inadvertently omitted.Jonghe, S. D.; Lamote, I.; Venkataraman, K,; Boldin, S. A.; Hillaert, U.; Rozenski, J.; Hendrix, C.; Busson, R.;Keukeleire, D. D.; Calenbergh, S. V.; Futerman, A. H.; Herdewijn, P. J. Org. Chem. 2002, 67, 988.