Discovery and synthesis of tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers

A novel class of tetrahydroindolone-derived semicarbazones has been discovered as potent Kv1.5 blockers. In in vitro studies, several compounds exhibited very good potency for blockade of Kv1.5. Compound 8i showed good selectivity for blockade of Kv1.5 vs hERG and L-type calcium channels. In an anesthetized pig model, compounds 8i and 10c increased atrial ERP about 28%, 18%, respectively, in the right atrium without affecting ventricular ERP.     

Brain evoked responses, a bioassay for central actions of adrenocorticotropin (ACTH 1-39) and corticotropin releasing hormone (CRH) in humans.

Blood borne hormones of the hypothalamus-pituitary-adrenal (HPA) axis form an afferent humoral system modulating a great variety of brain functions. In humans, bioassays consistently reflecting central nervous system actions have not been developed, so far. The present experiments are part of a series of studies which have been conducted to demonstrate the afferent influences of ACTH and CRH on brain activity by recording of auditory event-related brain potentials (ERPs) in healthy human subjects. In a double-blind within-subject comparison in 12 healthy male students, influences of 4 U ACTH and 100 micrograms CRH (infused within 2 h; the infusion starting 1 h prior to ERP recordings) were compared with the effects of a placebo infusion. Influences of the hormones were tested for the early, brain stem generated ERP components (BAEPs) and for the late components of the ERP associated with cortical stimulus processing. ACTH and CRH showed no consistent effect on BAEPs. ACTH, but not CRH, significantly reduced amplitudes of late ERP components, in particular, the Nd and P3 components which are considered signs of selective attention. These results are consistent with findings from previous studies demonstrating impaired ERP signs of selective attention in humans after administration of the 4-10 fragment of ACTH which lacks the peripheral adrenocorticotropic activity. Together with these foregoing studies, results from the present experiments further establish ERP methodology as a sensitive bioassay for CNS actions of hormones in humans.     

Classifying four-category visual objects using multiple ERP components in single-trial ERP

Object categorization using single-trial electroencephalography (EEG) data measured while participants view images has been studied intensively. In previous studies, multiple event-related potential (ERP) components (e.g., P1, N1, P2, and P3) were used to improve the performance of object categorization of visual stimuli. In this study, we introduce a novel method that uses multiple-kernel support vector machine to fuse multiple ERP component features. We investigate whether fusing the potential complementary information of different ERP components (e.g., P1, N1, P2a, and P2b) can improve the performance of four-category visual object classification in single-trial EEGs. We also compare the classification accuracy of different ERP component fusion methods. Our experimental results indicate that the classification accuracy increases through multiple ERP fusion. Additional comparative analyses indicate that the multiple-kernel fusion method can achieve a mean classification accuracy higher than 72 %, which is substantially better than that achieved with any single ERP component feature (55.07 % for the best single ERP component, N1). We compare the classification results with those of other fusion methods and determine that the accuracy of the multiple-kernel fusion method is 5.47, 4.06, and 16.90 % higher than those of feature concatenation, feature extraction, and decision fusion, respectively. Our study shows that our multiple-kernel fusion method outperforms other fusion methods and thus provides a means to improve the classification performance of single-trial ERPs in brain–computer interface research.     

The time course of the influence of valence and arousal on the implicit processing of affective pictures

In the current study, we investigated the time course of the implicit processing of affective pictures with an orthogonal design of valence (negative vs. positive) by arousal (low vs. high). Previous studies with explicit tasks suggested that valence mainly modulates early event-related potential (ERP) components, whereas arousal mainly modulates late components. However, in this study with an implicit task, we observed significant interactions between valence and arousal at both early and late stages over both parietal and frontal sites, which were reflected by three different ERP components: P2a (100-200 ms), N2 (200-300 ms), and P3 (300-400 ms). Furthermore, there was also a significant main effect of arousal on P2b (200-300 ms) over parieto-occipital sites. Our results suggest that valence and arousal effects on implicit affective processing are more complicated than previous ERP studies with explicit tasks have revealed.     

Amplitude modulation of steady-state visual evoked potentials by event-related potentials in a working memory task

Previous studies have shown that the amplitude and phase of the steady-state visual-evoked potential (SSVEP) can be influenced by a cognitive task, yet the mechanism of this influence has not been understood. As the event-related potential (ERP) is the direct neural electric response to a cognitive task, studying the relationship between the SSVEP and ERP would be meaningful in understanding this underlying mechanism. In this work, the traditional average method was applied to extract the ERP directly, following the stimulus of a working memory task, while a technique named steady-state probe topography was utilized to estimate the SSVEP under the simultaneous stimulus of an 8.3-Hz flicker and a working memory task; a comparison between the ERP and SSVEP was completed. The results show that the ERP can modulate the SSVEP amplitude, and for regions where both SSVEP and ERP are strong, the modulation depth is large.     

Erp1p and Erp2p, Partners for Emp24p and Erv25p in a Yeast p24 Complex

Six new members of the yeast p24 family have been identified and characterized. These six genes, named ERP1-ERP6 (for Emp24p- and Erv25p-related proteins) are not essential, but deletion of ERP1 or ERP2 causes defects in the transport of Gas1p, in the retention of BiP, and deletion of ERP1 results in the suppression of a temperature-sensitive mutation in SEC13 encoding a COPII vesicle coat protein. These phenotypes are similar to those caused by deletion of EMP24 or ERV25, two previously identified genes that encode related p24 proteins. Genetic and biochemical studies demonstrate that Erp1p and Erp2p function in a heteromeric complex with Emp24p and Erv25p.     

ERP57 membrane translocation dictates the immunogenicity of tumor cell death by controlling the membrane translocation of calreticulin

Several pieces of experimental evidence indicate the following: 1) the most efficient antitumor treatments (this principle applies on both chemotherapy and radiotherapy) are those that induce immunogenic cell death and are able to trigger a specific antitumor immune response; and 2) the immunogenicity of cell death depends very closely on the plasma membrane quantity of calreticulin (CRT), an endoplasmic reticulum (ER) stress protein exposed to the cell membrane after immunogenic treatment. Nevertheless, the mechanisms implicated in CRT translocation are unknown. CRT is known to interact in the ER with ERP57, another ER stress protein. I sought to determine whether ERP57 would have any role in tumor immunogenicity. In this article I report that CRT exposure is controlled by ERP57 exposure. CRT and ERP57 are translocated together in the same molecular complex. ERP57 knockdown suppressed CRT exposure as well as phagocytosis by dendritic cells and abolished the immunogenicity in vivo. Knockdown or the absence of CRT abolishes ERP57 exposure. Administration of recombinant ERP57, unlike the administration of recombinant CRT, did not restore the immunogenicity of CRT or ERP57 small interfering RNA-transfected tumor cells. Together, these studies identify ERP57 as a key protein that controls immunogenicity by controlling CRT exposure and illustrate the ability of ERP57 to serve as a new molecular marker of immunogenicity.     

Auditory ERPs to stimulus deviance in an awake chimpanzee (Pan troglodytes): towards hominid cognitive neurosciences

Background

For decades, the chimpanzee, phylogenetically closest to humans, has been analyzed intensively in comparative cognitive studies. Other than the accumulation of behavioral data, the neural basis for cognitive processing in the chimpanzee remains to be clarified. To increase our knowledge on the evolutionary and neural basis of human cognition, comparative neurophysiological studies exploring endogenous neural activities in the awake state are needed. However, to date, such studies have rarely been reported in non-human hominid species, due to the practical difficulties in conducting non-invasive measurements on awake individuals.

Methodology/Principal Findings

We measured auditory event-related potentials (ERPs) of a fully awake chimpanzee, with reference to a well-documented component of human studies, namely mismatch negativity (MMN). In response to infrequent, deviant tones that were delivered in a uniform sound stream, a comparable ERP component could be detected as negative deflections in early latencies.

Conclusions/Significance

The present study reports the MMN-like component in a chimpanzee for the first time. In human studies, various ERP components, including MMN, are well-documented indicators of cognitive and neural processing. The results of the present study validate the use of non-invasive ERP measurements for studies on cognitive and neural processing in chimpanzees, and open the way for future studies comparing endogenous neural activities between humans and chimpanzees. This signifies an essential step in hominid cognitive neurosciences.     

Target and Non-Target Processing during Oddball and Cyberball: A Comparative Event-Related Potential Study

The phenomenon of social exclusion can be investigated by using a virtual ball-tossing game called Cyberball. In neuroimaging studies, structures have been identified which are activated during social exclusion. But to date the underlying mechanisms are not fully disclosed. In previous electrophysiological studies it was shown that the P3 complex is sensitive to exclusion manipulations in the Cyberball paradigm and that there is a correlation between P3 amplitude and self-reported social pain. Since this posterior event-related potential (ERP) was widely investigated using the oddball paradigm, we directly compared the ERP effects elicited by the target (Cyberball: “ball possession”) and non-target (Cyberball: “ball possession of a co-player) events in both paradigms. Analyses mainly focused on the effect of altered stimulus probabilities of the target and non-target events between two consecutive blocks of the tasks. In the first block, the probability of the target and non-target event was 33% (Cyberball: inclusion), in the second block target probability was reduced to 17%, and accordingly, non-target probability was increased to 66% (Cyberball: exclusion). Our results indicate that ERP amplitude differences between inclusion and exclusion are comparable to ERP amplitude effects in a visual oddball task. We therefore suggest that ERP effects–especially in the P3 range–in the Oddball and Cyberball paradigm rely on similar mechanisms, namely the probability of target and non-target events. Since the simulation of social exclusion (Cyberball) did not trigger a unique ERP response, the idea of an exclusion-specific neural alarm system is not supported. The limitations of an ERP-based approach will be discussed.     

Individual Differences in the Recognition of Facial Expressions: An Event-Related Potentials Study

Previous studies have shown that early posterior components of event-related potentials (ERPs) are modulated by facial expressions. The goal of the current study was to investigate individual differences in the recognition of facial expressions by examining the relationship between ERP components and the discrimination of facial expressions. Pictures of 3 facial expressions (angry, happy, and neutral) were presented to 36 young adults during ERP recording. Participants were asked to respond with a button press as soon as they recognized the expression depicted. A multiple regression analysis, where ERP components were set as predictor variables, assessed hits and reaction times in response to the facial expressions as dependent variables. The N170 amplitudes significantly predicted for accuracy of angry and happy expressions, and the N170 latencies were predictive for accuracy of neutral expressions. The P2 amplitudes significantly predicted reaction time. The P2 latencies significantly predicted reaction times only for neutral faces. These results suggest that individual differences in the recognition of facial expressions emerge from early components in visual processing.     

Effects of the menstrual cycle on auditory event-related potentials

Gonadal steroids (estradiol and progesterone) can alter neuronal functioning, but electrophysiological evidence in women is still sparse. Therefore, the present study investigated event-related potentials (ERPs) to neutral stimuli over the course of the menstrual cycle. In addition, associations between ERPs and salivary estradiol and progesterone concentrations were investigated. Eighteen young healthy women were tested at three different phases of their menstrual cycle (menses, and follicular and luteal phases). ERPs (i.e., the N1 and P2 components, reflecting cortical arousal and the orienting response, the N2, P3, and the Slow Wave (SW), reflecting controlled processing) were measured using two different paradigms. In the luteal phase, early ERPs reflecting the cortical arousal response were diminished in the first stimulus block indicating an attenuated orienting response. These changes were significantly correlated with estradiol as well as progesterone levels. As to the later ERP components, the N2 latency was shorter during menses compared to the other two phases. No menstrual cycle-associated changes were apparent in other late ERP components. In sum, this study documents changes in auditory ERPs across the menstrual cycle with the most prominent changes occurring during the luteal phase. Future ERP studies therefore need to be more attentive to the issue of menstrual phase when studying female subjects or female patients.     

Multi-representation of symbolic and nonsymbolic numerical magnitude in Chinese number processing

Numerical information can be conveyed by either symbolic or nonsymbolic representation. Some symbolic numerals can also be identified as nonsymbolic quantities defined by the number of lines (e.g., I, II, III in Roman and -, =, ≡ in Japanese Kanji and Chinese). Here we report that such multi-representation of magnitude can facilitate the processing of these numerals under certain circumstances. In a magnitude comparison task judging 1 to 9 (except 5) Chinese and Arabic numerals presented at the foveal (at the center) or parafoveal (3° left or right of the center) location, multi-representational small-value Chinese numerals showed a processing advantage over single-representational Arabic numerals and large-value Chinese numerals only in the parafoveal condition, demonstrated by lower error rates and faster reaction times. Further event-related potential (ERP) analysis showed that such a processing advantage was not reflected by traditional ERP components identified in previous studies of number processing, such as N1 or P2p. Instead, the difference was found much later in a N400 component between 300-550 msec over parietal regions, suggesting that those behavioral differences may not be due to early processing of visual identification, but later processing of subitizing or accessing mental number line when lacking attentional resources. These results suggest that there could be three stages of number processing represented separately by the N1, P2p and N400 ERP components. In addition, numerical information can be represented simultaneously by both symbolic and nonsymbolic systems, which will facilitate number processing in certain situations.     

Reflection of working memory: ERP mnemonic effects

The study of working memory often utilizes a delayed matching to sample paradigm (DMS). Typically in the matching condition, the test and sample stimuli are identical, raising the possible confound of retinotopic projections for the matching stimuli in contrast to the non-matching stimuli. In the present study, 65 healthy subjects performed a modified delayed matching to sample task while monitoring their ERP waveforms. The stimuli consisted of 60 different sample stimuli (S1) and 60 different test stimuli (S2). Half of the S2s were complementary to the sample stimuli (Fit), the other half of the S2s were not complementary (Nonfit). After S2, the subjects pressed one of the buttons to indicate whether the test stimulus fits the sample stimulus. Our statistical results indicated that the ERPs to sample stimuli differed from the ERPs to test stimuli from 200 ms poststimulus to the end of the recording epoch. The ERPs to fitting stimuli were significantly different from those to non-fitting stimuli from 200 to 400 ms poststimulus. The ERP patterns in the present study may reflect ERP mnemonic effect for working memory. Our results ruled out the retinotopic confound as a potential mediator variable, and are in agreement with other animal or human neurophysiological studies on memory.     

生态系统服务研究在生态红线政策保护成效评估中的应用

生态保护红线政策是中国推进生态保护与建设的宏观政策,其保护成效评估是国内外关注的重大科学问题。在分析国内外生态系统服务研究进展及中国生态保护红线内涵、划定进程及管控要求的基础上,结合生态红线政策与生态系统服务研究的关联及生态系统服务研究在红线政策保护成效评估应用中面临的挑战,提出了红线政策实施效果评估的技术框架和基本思路。开展生态红线政策保护成效评估,能从科学上明确生态红线政策实施对多尺度利益相关者成本、效益的影响,为生态红线政策的综合研究提供框架和科学方法;从政策设计上,为生态红线布局进一步优化提供依据;从制度建设上,提出符合生态红线政策实施的制度框架,推动生态保护红线制度建设由理论走向实践。     

Quantitative trait loci analysis of human event-related brain potentials: P3 voltage

The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded electroencephalographic activity that occurs between 300–500 ms after stimulus onset. It is elicited when a stimulus is perceived, memory operations are engaged, and attentional resources are allocated toward its processing. Because this ERP component reflects fundamental cognitive processing, it has found wide utility as an assessment of human mental function in basic and clinical studies. In particular, P3 attributes are heritable and have demonstrated considerable promise as a means to identify individuals at genetic risk for alcoholism. We have conducted a quantitative linkage analysis on a large sample from families with a high density of affected individuals. The analyses suggest that several regions of the human genome contain genetic loci related to the generation of the P3 component of the ERP, which are possible candidate loci underlying the functional organization of human neuroelectric activity.     

Electrical refractory period restitution and spiral wave reentry in simulated cardiac tissue

Theoretical and experimental studies have shown that restitution of the cardiac action potential (AP) duration (APD) plays a major role in predisposing ventricular tachycardia to degenerate to ventricular fibrillation, whereas its role in atrial fibrillation is unclear. We used the Courtemanche human atrial cell model and the Luo-Rudy guinea pig ventricular model to compare the roles of electrical restitution in destabilizing spiral wave reentry in simulated two-dimensional homogeneous atrial and ventricular tissue. Because atrial AP morphology is complex, we also validated the usefulness of effective refractory period (ERP) restitution. ERP restitution correlated best with APD restitution at transmembrane potentials greater than or equal to -62 mV, and its steepness was a reliable predictor of spiral wave phenotype (stable, meandering, hypermeandering, and breakup) in both atrial and ventricular tissue. Spiral breakup or single hypermeandering spirals occurred when the slope of ERP restitution exceeded 1 at short diastolic intervals. Thus ERP restitution, which is easier to measure clinically than APD restitution, is a reliable determinant of spiral wave stability in simulated atrial and ventricular tissue.     

A peptide secreted by human alveolar macrophages releases neutrophil granule contents

A monoclonal antibody was developed against an 8,000-kDa enzyme-releasing peptide (ERP) released from human alveolar macrophages. ERP was isolated on an immunoaffinity column containing the antibody bound to staphylococcal protein A-Sepharose. Release of ERP from the macrophages is not changed by plastic adherence, phagocytosis, calcium ionophore, or phorbol esters. The peptide was not antigenically similar to interferon-gamma, tumor necrosis factor, or interleukin 1 alpha or 1 beta. The release of constituents from azurophilic and specific granules was the main identified biologic function of ERP. ERP was a more effective secretagogue in the untreated neutrophils and f-met-leu-phe was more effective in the cytochalasin B-treated neutrophils. Absorption of ERP from macrophage-conditioned medium removed a small amount of the chemotactic activity; however, the immunopurified peptide was not chemotactic or chemokinetic for neutrophils, and at high concentrations, it suppressed base line chemokinesis. Treatment of washed macrophages with trypsin released active ERP of approximately the same m.w. of spontaneously secreted ERP. These studies showed that human alveolar macrophages release a peptide which is a secretagogue for human neutrophils under conditions which may be encountered in the lungs during certain disease states. Proteolytic enzymes which are free in the lungs may release the peptide and lead to the secretion of neutrophil enzymes.     

The cortical interactions in short time intervals during the search for verbal associations

Cortical connectivity was studied in tasks of generating the use of words in comparison with reading aloud the same words. These tasks were used earlier in PET and high-density ERP recording studies, which described both the functional anatomy and time course of involvement of cortical areas in word processing. We developed a new method for studying the synchrony of EEG spectral components within the short time intervals compatible with the duration of particular cognitive operations. The wavelet transform of the ERP records and calculation of correlations between the wavelet curves were used to reveal connections between cortical areas. Three stages of intracortical communications developing over the course of task performance were discovered: between the right and left frontal areas (0-200 ms after the stimulus presentation), between the left frontal and left posterior temporo-parietal areas (250-500 ms), and, finally, between the left temporal and right fronto-centro-temporal areas. These findings are in good agreement with the results of the previous PET and ERP studies and supplement them with the circuitry of cortical information transfer. Also, they suggest some differences in information processing during automated reading and performance of more complicated use-generation task.     

Event-related Potential Study of Novelty Processing Abnormalities in Autism

To better understand visual processing abnormalities in autism we studied the attention orienting related frontal event potentials (ERP) and the sustained attention related centro-parietal ERPs in a three stimulus oddball experiment. The three stimulus oddball paradigm was aimed to test the hypothesis that individuals with autism abnormally orient their attention to novel distracters as compared to controls. A dense-array 128 channel EGI electroencephalographic (EEG) system was used on 11 high-functioning children and young adults with autism spectrum disorder (ASD) and 11 age-matched, typically developing control subjects. Patients with ASD showed slower reaction times but did not differ in response accuracy. At the anterior (frontal) topography the ASD group showed significantly higher amplitudes and longer latencies of early ERP components (e.g., P100, N100) to novel distracter stimuli in both hemispheres. The ASD group also showed prolonged latencies of late ERP components (e.g., P2a, N200, P3a) to novel distracter stimuli in both hemispheres. However, differences were more profound in the right hemisphere for both early and late ERP components. Our results indicate augmented and prolonged early frontal potentials and a delayed P3a component to novel stimuli, which suggest low selectivity in pre-processing and later-stage under-activation of integrative regions in the prefrontal cortices. Also, at the posterior (centro-parietal) topography the ASD group showed significantly prolonged N100 latencies and reduced amplitudes of the N2b component to target stimuli. In addition, the latency of the P3b component was prolonged to novel distracters in the ASD group. In general, the autistic group showed prolonged latencies to novel stimuli especially in the right hemisphere. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. We propose the potential application of ERP evaluations in a novelty task as outcome measurements in the biobehavioral treatment (e.g., EEG biofeedback, TMS) of autism.