NMDAR/PKC通路介导基底外侧杏仁核的长时程增强

本文在大鼠杏仁核脑片上刺激外囊（external capsule,EC）,在基底外侧杏仁核（basolateral amygdala,BLA）记录场电位,观察能否在杏仁核诱导长时程增强（long—term potentiation,LTP）,并探讨杏仁核LTP形成的可能机制。应用两串间隔10min的0频率波刺激EC,可见BLA的场电位明显增强,持续时间在30min以上。EC—BLA的LTP表现为通路特异性,可被N-甲基-D-天冬氨酸受体（N-methyl—D—aspartate receptor,NMDAR）阻断剂D,L-2-氨基-5磷酸基戊酸（APV）阻断。在灌流液中加入蛋白激酶C（protein kinaseC,PKC）抑制剂chelerythrine chloride,对BLA的基础场电位和配对脉冲比率（pairedpulse ratio,PPR）没有影响;但在chelerythrine chloride存在的情况下,两串θ频率波刺激不能诱导出LTP;若于两串高频刺激10min后,在灌流液中加入chelerythrine chloride不能阻断BLA的LTP。上述结果表明,EC—BLA的LTP为NMDAR依赖性,PKC参与BLA的LTP诱导和早期维持。     

Reduced C(beta) statistical potentials can outperform all-atom potentials in decoy identification

We developed a series of statistical potentials to recognize the native protein from decoys, particularly when using only a reduced representation in which each side chain is treated as a single C(beta) atom. Beginning with a highly successful all-atom statistical potential, the Discrete Optimized Protein Energy function (DOPE), we considered the implications of including additional information in the all-atom statistical potential and subsequently reducing to the C(beta) representation. One of the potentials includes interaction energies conditional on backbone geometries. A second potential separates sequence local from sequence nonlocal interactions and introduces a novel reference state for the sequence local interactions. The resultant potentials perform better than the original DOPE statistical potential in decoy identification. Moreover, even upon passing to a reduced C(beta) representation, these statistical potentials outscore the original (all-atom) DOPE potential in identifying native states for sets of decoys. Interestingly, the backbone-dependent statistical potential is shown to retain nearly all of the information content of the all-atom representation in the C(beta) representation. In addition, these new statistical potentials are combined with existing potentials to model hydrogen bonding, torsion energies, and solvation energies to produce even better performing potentials. The ability of the C(beta) statistical potentials to accurately represent protein interactions bodes well for computational efficiency in protein folding calculations using reduced backbone representations, while the extensions to DOPE illustrate general principles for improving knowledge-based potentials.     

False belief reasoning in the brain: An ERP study

Understanding others mind and interpersonal interaction are the cognitive basis of successful social interactions. People's mental states and behaviors rely on their holding beliefs for self and others. To investigate the neural substrates of false belief reasoning, the 32 channels event-related potentials (ERP) of 14 normal adults were measured while they understood false-belief and true belief used de-ceptive appearance task. After onset of the false-belief or true-belief questions, N100, P200 and late negative component (LNC) were elicited at centro-frontal sites. Compared with true belief, false belief reasoning elicited significant declined LNC in the time window from 400 to 800 ms. The source analysis of difference wave (False minus True) showed a dipole located in the middle cingulated cortex. These findings show that false belief reasoning probably included inhibitive process.     

Progress in fold recognition

The prediction experiment reveals that fold recognition has become a powerful tool in structural biology. We applied our fold recognition technique to 13 target sequences. In two cases, replication terminating protein and prosequence of subtilisin, the predicted structures are very similar to the experimentally determined folds. For the first time, in a public blind test, the unknown structures of proteins have been predicted ahead of experiment to an accuracy approaching molecular detail. In two other cases the approximate folds have been predicted correctly. According to the assessors there were 12 recognizable folds among the target proteins. In our postprediction analysis we find that in 7 cases our fold recognition technique is successful. In several of the remaining cases the predicted folds have interesting features in common with the experimental results. We present our procedure, discuss the results, and comment on several fundamental and technical problems encountered in fold recognition. © 1995 Wiley-Liss, Inc.     

Event-related potentials in a Go/Nogo task of abnormal response inhibition in heroin addicts

Inhibitory control dysfunction is regarded as a core feature in addicts. The major objective of this study was to explore the time course of response inhibition in chronic heroin addicts and provide the neu-rophysiological evidence of their inhibitory control dysfunction. The amplitudes and latencies of ERP components were studied in fourteen heroin addicts (mean duration of heroin use being (13.54±5.71) years (Mean±SD), average abstinence being ((4.67±6.44) months)) and fourteen matched healthy con-trols with a visual Go/Nogo task. Our results showed that heroin addicts demonstrated significantly larger Go-N2 amplitudes which results in a decreased N2 Go/Nogo effect, but no statistically significant differences were found between heroin addicts and controls in P3. The ERP data suggest that fronto-central areas of heroin addicts were impaired during the inhibition process (200—300 ms) and over-activated to targets. The impaired early process might reflect an abnormal conflict monitoring process in heroin addicts. These results consolidate the inhibitory control dysfunction hypothesis in chronic heroin users.     

Effects of 45-Hz magnetic fields on the functional state of the human brain

The influence of sinusoidal 45-Hz magnetic fields on the brain functions of 20 volunteers was investigated in a double-blind study using spectral analysis of EEG and measurements of Omega potentials and reaction time (RT). The field strength was 1,000 A/m (1.26 mT) and the duration of exposure was 1 h. Ten volunteers were exposed to a continuous field and ten received an intermittent exposure (1 s on/1 s off). Each person received one real and one sham exposure. One half of the volunteers got the real exposure first and the sham treatment after at least 24 h. For the rest, the sequence was inverse. The measurements of EEG, omega potentials and RT were performed before and after each exposure. Several statistically significant changes were observed, most of them after intermittent exposure. In the EEG, an increase of alpha (7.6–13.9 Hz) activity and a decrease of delta (1.5–3.9 Hz) activity were observed. β waves (14.2–20 Hz) increased in the frontal derivations as did the total power in occipital derivations. The mean and peak frequencies of EEG increased mainly in the frontal derivations. No direct effects on RT were seen. Learning to perform the RT test (decrease of RT in repeated trials), however, seemed to be affected by the exposure. The persons who received real exposure first learned more slowly than those who got sham exposure first. Further experiments are necessary to confirm the findings and for understanding the mechanisms of the effects. © 1993 Wiley-Liss. Inc.     

Pair potentials for protein folding: choice of reference states and sensitivity of predicted native states to variations in the interaction schemes

We examine the similarities and differences between two widely used knowledge-based potentials, which are expressed as contact matrices (consisting of 210 elements) that gives a scale for interaction energies between the naturally occurring amino acid residues. These are the Miyazawa-Jernigan contact interaction matrix M and the potential matrix S derived by Skolnick J et al., 1997, Protein Sci 6:676-688. Although the correlation between the two matrices is good, there is a relatively large dispersion between the elements. We show that when Thr is chosen as a reference solvent within the Miyazawa and Jernigan scheme, the dispersion between the M and S matrices is reduced. The resulting interaction matrix B gives hydrophobicities that are in very good agreement with experiment. The small dispersion between the S and B matrices, which arises due to differing reference states, is shown to have dramatic effect on the predicted native states of lattice models of proteins. These findings and other arguments are used to suggest that for reliable predictions of protein structures, pairwise additive potentials are not sufficient. We also establish that optimized protein sequences can tolerate relatively large random errors in the pair potentials. We conjecture that three body interaction may be needed to predict the folds of proteins in a reliable manner.     

Changes in EEG Power Spectra During Biofeedback of Slow Cortical Potentials in Epilepsy

The goal of the study was to explore parallel changes in EEG spectral frequencies during biofeedback of slow cortical potentials (SCPs) in epilepsy patients. Thirty-four patients with intractable focal epilepsy participated in 35 sessions of SCP self-regulation training. The spectral analysis was carried out for the EEG recorded at the same electrode site (Cz) that was used for SCP feedback. The most prominent effect was the increase in the 2 power (6.0–7.9 Hz) and the relative power decrement in all other frequency bands (particularly 1, 2, and 2) in transfer trials (i.e., where patients controlled their SCPs without continuous feedback) compared with feedback trials. In the second half of the training course (i.e., sessions 21–35) larger power values in the , , and bands were found when patients were required to produce positive versus negative SCP shifts. Both across-subject and across-session (within-subject) correlations between spectral EEG parameters, on the one hand, and SCP data, on the other hand, were low and inconsistent, contrary to high and stable correlations between different spectral variables. This fact, as well as the lack of considerable task-dependent effects during the first part of training, indicates that learned SCP shifts did not directly lead to the specific dynamics of the EEG power spectra. Rather, these dynamics were related to nonspecific changes in patients' brain state.     

Molecular recognition of aldehydes by aldehyde dehydrogenase and mechanism of nucleophile activation

Experimental structural data on the state of substrates bound to class 3 Aldehyde Dehydrogenases (ALDH3A1) is currently unknown. We have utilized molecular mechanics (MM) simulations, in conjunction with new force field parameters for aldehydes, to study the atomic details of benzaldehyde binding to ALDH3A1. Our results indicate that while the nucleophilic Cys243 must be in the neutral state to form what are commonly called near-attack conformers (NACs), these structures do not correlate with increased complexation energy calculated with the MM-Generalized Born Molecular Volume (GBMV) method. The negatively charged Cys243 (thiolate form) of ALDH3A1 also binds benzaldehyde in a stable conformation but in this complex the sulfur of Cys243 is oriented away from benzaldehyde yet yields the most favorable MM-GBMV complexation energy. The identity of the general base, Glu209 or Glu333, in ALDHs remains uncertain. The MM simulations reveal structural and possible functional roles for both Glu209 and Glu333. Structures from the MM simulations that would support either glutamate residue as the general base were further examined with Hybrid Quantum Mechanical (QM)/MM simulations. These simulations show that, with the PM3/OPLS potential, Glu209 must go through a step-wise mechanism to activate Cys243 through an intervening water molecule while Glu333 can go through a more favorable concerted mechanism for the same activation process.