Scaffold-Hopped Compound Identification by Ligand-Based Approaches with a Prospective Affinity Test.

Scaffold-hopped (SH) compounds are bioactive compounds structurally different from known active compounds. Identifying SH compounds in the ligand-based approaches has been a central issue in medicinal chemistry, and various molecular representations of scaffold hopping have been proposed. However, appropriate representations for SH compound identification remain unclear. Herein, the ability of SH compound identification among several representations was fairly evaluated based on retrospective validation and prospective demonstration. In the retrospective validation, the combinations of two screening algorithms and four two- and three-dimensional molecular representations were compared using controlled data sets for the early identification of SH compounds. We found that the combination of the support vector machine and extended connectivity fingerprint with bond diameter 4 (SVM-ECFP4) and SVM and the rapid overlay of chemical structures (SVM-ROCS) showed a relatively high performance. The compounds that were highly ranked by SVM-ROCS did not share substructures with the active training compounds, while those ranked by SVM-ECFP4 were mostly recombinant. In the prospective demonstration, 93 SH compounds were prepared by screening the Namiki database using SVM-ROCS, targeting ABL1 inhibitors. The primary screening using surface plasmon resonance suggested five active compounds; however, in the competitive binding assays with adenosine triphosphate, no hits were found.

Aberrant thalamocortical connectivity and shifts between the resting state and task state in patients with schizophrenia.

Prominent pathological hypotheses for schizophrenia include auditory processing deficits and dysconnectivity within cerebral networks. However, most neuroimaging studies have focused on impairments in either resting-state or task-related functional connectivity in patients with schizophrenia. The aims of our study were to examine (1) blood oxygen level-dependent (BOLD) signals during auditory steady-state response (ASSR) tasks, (2) functional connectivity during the resting-state and ASSR tasks and (3) state shifts between the resting-state and ASSR tasks in patients with schizophrenia. To reduce the functional consequences of scanner noise, we employed resting-state and sparse sampling auditory fMRI paradigms in 25 schizophrenia patients and 25 healthy controls. Auditory stimuli were binaural click trains at frequencies of 20, 30, 40 and 80 Hz. Based on the detected ASSR-evoked BOLD signals, we examined the functional connectivity between the thalamus and bilateral auditory cortex during both the resting state and ASSR task state, as well as their alterations. The schizophrenia group exhibited significantly diminished BOLD signals in the bilateral auditory cortex and thalamus during the 80 Hz ASSR task (corrected p < 0.05). We observed a significant inverse relationship between the resting state and ASSR task state in altered functional connectivity within the thalamo-auditory network in schizophrenia patients. Specifically, our findings demonstrated stronger functional connectivity in the resting state (p < 0.004) and reduced functional connectivity during the ASSR task (p = 0.048), which was mediated by abnormal state shifts, within the schizophrenia group. These results highlight the presence of abnormal thalamocortical connectivity associated with deficits in the shift between resting and task states in patients with schizophrenia.

Abnormal connectivity and activation during audiovisual speech perception in schizophrenia.

The unconscious integration of vocal and facial cues during speech perception facilitates face-to-face communication. Recent studies have provided substantial behavioural evidence concerning impairments in audiovisual (AV) speech perception in schizophrenia. However, the specific neurophysiological mechanism underlying these deficits remains unknown. Here, we investigated activities and connectivities centered on the auditory cortex during AV speech perception in schizophrenia. Using magnetoencephalography, we recorded and analysed event-related fields in response to auditory (A: voice), visual (V: face) and AV (voice-face) stimuli in 23 schizophrenia patients (13 males) and 22 healthy controls (13 males). The functional connectivity associated with the subadditive response to AV stimulus (i.e., [AV] < [A] + [V]) was also compared between the two groups. Within the healthy control group, [AV] activity was smaller than the sum of [A] and [V] at latencies of approximately 100 ms in the posterior ramus of the lateral sulcus in only the left hemisphere, demonstrating a subadditive N1m effect. Conversely, the schizophrenia group did not show such a subadditive response. Furthermore, weaker functional connectivity from the posterior ramus of the lateral sulcus of the left hemisphere to the fusiform gyrus of the right hemisphere was observed in schizophrenia. Notably, this weakened connectivity was associated with the severity of negative symptoms. These results demonstrate abnormalities in connectivity between speech- and face-related cortical areas in schizophrenia. This aberrant subadditive response and connectivity deficits for integrating speech and facial information may be the neural basis of social communication dysfunctions in schizophrenia.

Abnormal phase entrainment of low- and high-gamma-band auditory steady-state responses in schizophrenia.

Introduction: Gamma-band oscillatory deficits have attracted considerable attention as promising biomarkers of schizophrenia (SZ). Notably, a reduced auditory steady-state response (ASSR) in the low gamma band (40 Hz) is widely recognized as a robust finding among SZ patients. However, a comprehensive investigation into the potential utility of the high-gamma-band ASSR in detecting altered neural oscillations in SZ has not yet been conducted. Methods: The present study aimed to assess the ASSR using magnetoencephalography (MEG) data obtained during steady-state stimuli at frequencies of 20, 30, 40, and 80 Hz from 23 SZ patients and 21 healthy controls (HCs). To evaluate the ASSR, we examined the evoked power and phase-locking factor (PLF) in the time-frequency domain for both the primary and secondary auditory cortices. Furthermore, we calculated the phase-locking angle (PLA) to examine oscillatory phase lead or delay in SZ patients. Taking advantage of the high spatial resolution of MEG, we also focused on the hemispheric laterality of low- and high-gamma-band ASSR deficits in SZ. Results: We found abnormal phase delay in the 40 Hz ASSR within the bilateral auditory cortex of SZ patients. Regarding the 80 Hz ASSR, our investigation identified an aberrant phase lead in the left secondary auditory cortex in SZ, accompanied by reduced evoked power in both auditory cortices. Discussion: Given that abnormal phase lead on 80 Hz ASSR exhibited the highest discriminative power between HC and SZ, we propose that the examination of PLA in the 80 Hz ASSR holds significant promise as a robust candidate for identifying neurophysiological endophenotypes associated with SZ. Furthermore, the left-hemisphere phase lead observed in the deficits of 80 Hz PLA aligns with numerous prior studies, which have consistently proposed that SZ is characterized by left-lateralized brain dysfunctions.

Cortical representation of speech temporal information through high gamma-band activity and its temporal modulation.

Numerous studies have investigated low-frequency (theta-band) and high-frequency (gamma-band) neural activities that are phase-locked to temporal structures, including the temporal envelope and fine structure (TFS) of speech signals. Nonetheless, the neural mechanisms underlying the interaction between envelope and TFS processing remain elusive. Here we examined high gamma-band activities and their low-frequency amplitude modulations while listening to monotone speech (MS) with a fundamental frequency (F0) of 80 Hz and non-speech sounds with similar temporal characteristics to MS, namely an amplitude-modulated click train (AMC). Additionally, we utilized noise-vocoded speech (NVS) to evaluate the impact of eliminating the TFS from MS on the high gamma-band activity. We observed discernible high gamma-band activity at the same frequency as F0 of MS and the train frequency of AMC (80 Hz). Furthermore, source localization analysis revealed that the high gamma-band activities exhibited left hemisphere dominance in both MS and AMC conditions. Finally, high gamma-band activities exhibited amplitude-modulation at the same rate as the stimulus envelope of MS and AMC (5 Hz), though such modulation was not observed in NVS. Our findings indicate that the high gamma-band activity in the left hemisphere is pivotal in the interaction of envelope and TFS information processing, regardless of the nature of the stimulus being speech or non-speech.

Large-scale prediction of activity cliffs using machine and deep learning methods of increasing complexity.

Activity cliffs (AC) are formed by pairs of structural analogues that are active against the same target but have a large difference in potency. While much of our knowledge about ACs has originated from the analysis and comparison of compounds and activity data, several studies have reported AC predictions over the past decade. Different from typical compound classification tasks, AC predictions must be carried out at the level of compound pairs representing ACs or nonACs. Most AC predictions reported so far have focused on individual methods or comparisons of two or three approaches and only investigated a few compound activity classes (from 2 to 10). Although promising prediction accuracy has been reported in most cases, different system set-ups, AC definitions, methods, and calculation conditions were used, precluding direct comparisons of these studies. Therefore, we have carried out a large-scale AC prediction campaign across 100 activity classes comparing machine learning methods of greatly varying complexity, ranging from pair-based nearest neighbor classifiers and decision tree or kernel methods to deep neural networks. The results of our systematic predictions revealed the level of accuracy that can be expected for AC predictions across many different compound classes. In addition, prediction accuracy did not scale with methodological complexity but was significantly influenced by memorization of compounds shared by different ACs or nonACs. In many instances, limited training data were sufficient for building accurate models using different methods and there was no detectable advantage of deep learning over simpler approaches for AC prediction. On a global scale, support vector machine models performed best, by only small margins compared to others including simple nearest neighbor classifiers.

Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia.

BACKGROUND: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. METHOD: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. RESULTS: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. CONCLUSION: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

Decreased cortical gyrification and surface area in the left medial parietal cortex in patients with treatment-resistant and ultratreatment-resistant schizophrenia.

AIM: Validating the vulnerabilities and pathologies underlying treatment-resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS. METHODS: We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first-line antipsychotics (FL-Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ-Resp) and 22 FL- and clozapine-resistant patients (patients with ultratreatment-resistant schizophrenia [URS]). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis. RESULTS: Both CLZ-Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [gH ] = 0.75; P = 0.013, gH  = 0.96) and FL-Resp (P = 0.007, gH  = 1.00; P = 0.002, gH  = 1.31) in the left medial parietal cortex (Lt-MPC). In addition, both CLZ-Resp and URS had lower SA in the Lt-MPC than FL-Resp (P < 0.001, gH  = 1.22; P < 0.001, gH  = 1.75). LGI and SA were positively correlated in non-TRS (FL-Resp) (ρ = 0.64, P = 0.008) and TRS (CLZ-Resp + URS) (ρ = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non-TRS versus TRS with LGI and SA in the Lt-MPC were 0.79 and 0.85, respectively. SA in the Lt-MPC was inversely correlated with negative symptoms (ρ = -0.40, P = 0.018) and clozapine plasma levels (ρ = -0.35, P = 0.042) in TRS. CONCLUSION: LGI and SA in the Lt-MPC, a functional hub in the default-mode network, were abnormally reduced in TRS compared with non-TRS. Thus, altered LGI and SA in the Lt-MPC might be structural features associated with genetic vulnerability to TRS.

The clinical benefits of performing staging laparoscopy for pancreatic cancer treatment.

BACKGROUND: The indications and benefits derived from staging laparoscopy (SL) for pancreatic cancer (PC) remain controversial. METHODS: This study involved PC patients in whom resection had been considered possible between 2009 and 2020. We classified the patients into before 2014 (training set) and 2014 and later (validation set) groups, as SL was introduced in 2014, in our institution. In the training set, the predictors of non-curative factors were investigated, and reproducibility was confirmed in the validation set. In addition, the outcomes were compared between the datasets. RESULTS: A total of 802 patients were classified into the training set (n = 241) and validation set (n = 561). In the training set, pancreatic body or tail tumors (odds ratio [OR]: 2.62: P = 0.039), CA19-9 > 88 U/ml (OR: 3.21: P = 0.018) and a tumor diameter >36 mm (OR: 6.07; P < 0.001) were independent predictors of non-curative factors. The increased rate of non-curative factors was confirmed as the number of predictors increased in the validation set. The curative resection (CR) rate was significantly higher in the validation set than in the training set (P = 0.035). Although there was no significant difference in the OS in the not-resected group (P = 0.895), the OS in the CR and non-CR group was significantly better in the validation set than in the training set (CR, P < 0.001; non-CR, P < 0.001). CONCLUSION: The findings suggest potential candidates for SL and revealed improved outcomes by the advent of treatment strategies including SL.

Ligand-based approaches to activity prediction for the early stage of structure-activity-relationship progression.

The retrospective evaluation of virtual screening approaches and activity prediction models are important for methodological development. However, for fair comparison, evaluation data sets must be carefully prepared. In this research, we compiled structure-activity-relationship matrix-based data sets for 15 biological targets along with many diverse inactive compounds, assuming the early stage of structure-activity-relationship progression. To use a large number of diverse inactive compounds and a limited number of active compounds, similarity profiles (SPs) are proposed as a set of molecular descriptors. Using these highly imbalanced data sets, we evaluated various approaches including SPs, under-sampling, support vector machine (SVM), and message passing neural networks. We found that for the under-sampling approaches, cluster-based sampling is better than random sampling. For virtual screening, SPs with inactive reference compounds and the under-sampling SVM also perform well. For classification, SPs with many inactive references performed as well as the under-sampling SVM trained on a balanced data set. Although the performance of SPs and the under-sampling SVM were comparable, SPs with many inactive references were preferable for selecting structurally distinct compounds from the active training compounds.

Multi-modal imaging of the auditory-larynx motor network for voicing perception.

Voicing is one of the most important characteristics of phonetic speech sounds. Despite its importance, voicing perception mechanisms remain largely unknown. To explore auditory-motor networks associated with voicing perception, we firstly examined the brain regions that showed common activities for voicing production and perception using functional magnetic resonance imaging. Results indicated that the auditory and speech motor areas were activated with the operculum parietale 4 (OP4) during both voicing production and perception. Secondly, we used a magnetoencephalography and examined the dynamical functional connectivity of the auditory-motor networks during a perceptual categorization task of /da/-/ta/ continuum stimuli varying in voice onset time (VOT) from 0 to 40 ms in 10 ms steps. Significant functional connectivities from the auditory cortical regions to the larynx motor area via OP4 were observed only when perceiving the stimulus with VOT 30 ms. In addition, regional activity analysis showed that the neural representation of VOT in the auditory cortical regions was mostly correlated with categorical perception of voicing but did not reflect the perception of stimulus with VOT 30 ms. We suggest that the larynx motor area, which is considered to play a crucial role in voicing production, contributes to categorical perception of voicing by complementing the temporal processing in the auditory cortical regions.

Late responses in the anterior insula reflect the cognitive component of pain: evidence of nonpain processing.

INTRODUCTION: Pain is a complex experience influenced by sensory and psychological factors. The insula is considered to be a core part of the pain network in the brain. Previous studies have suggested a relationship between the posterior insula (PI) and sensory processing, and between the anterior insula (AI) and cognitive-affective factors. OBJECTIVES: Our aim was to distinguish sensory and cognitive responses in pain-related insular activities. METHODS: We recorded spatiotemporal insular activation patterns of healthy participants (n = 20) during pain or tactile processing with painful or nonpainful movie stimuli, using a magnetoencephalography. We compared the peak latency between PI and AI activities in each stimulus condition, and between pain and tactile processing in each response. The peak latency and amplitude between different movies were then examined to explore the effects of cognitive influence. A visual analogue scale was used to assess subjective perception. RESULTS: The results revealed one clear PI activity and 2 AI activities (early and late) in insular responses induced by pain/tactile stimulation. The early response transmitted from the PI to AI was observed during sensory-associated brain activity, whereas the late AI response was observed during cognitive-associated activity. In addition, we found that painful movie stimuli had a significant influence on both late AI activity and subjective perception, caused by nonpainful actual stimulation. CONCLUSIONS: The current findings suggested that late AI activation reflects the processing of cognitive pain information, whereas the PI and early AI responses reflect sensory processing.

Interpretation of Ligand-Based Activity Cliff Prediction Models Using the Matched Molecular Pair Kernel.

Activity cliffs (ACs) are formed by two structurally similar compounds with a large difference in potency. Accurate AC prediction is expected to help researchers' decisions in the early stages of drug discovery. Previously, predictive models based on matched molecular pair (MMP) cliffs have been proposed. However, the proposed methods face a challenge of interpretability due to the black-box character of the predictive models. In this study, we developed interpretable MMP fingerprints and modified a model-specific interpretation approach for models based on a support vector machine (SVM) and MMP kernel. We compared important features highlighted by this SVM-based interpretation approach and the SHapley Additive exPlanations (SHAP) as a major model-independent approach. The model-specific approach could capture the difference between AC and non-AC, while SHAP assigned high weights to the features not present in the test instances. For specific MMPs, the feature weights mapped by the SVM-based interpretation method were in agreement with the previously confirmed binding knowledge from X-ray co-crystal structures, indicating that this method is able to interpret the AC prediction model in a chemically intuitive manner.

Recent findings on neurofeedback training for auditory hallucinations in schizophrenia.

PURPOSE OF REVIEW: To provide recent evidence on real-time neurofeedback (NFB) training for auditory verbal hallucinations (AVH) in schizophrenia patients. RECENT FINDINGS: NFB is a promising technique that allows patients to gain control over their AVH by modulating their own speech-related/language-related networks including superior temporal gyrus (STG) and anterior cingulate cortex (ACC) using fMRI, fNIRS and EEG/MEG. A recent limited number of studies showed that while an EEG-based NFB study failed to regulate auditory-evoked potentials and reduce AVH, downregulation of STG hyperactivity and upregulation of ACC activity with fMRI-based NFB appear to alleviate treatment-resistant AVH in schizophrenia patients. A deeper understanding of AVH and development of more effective methodologies are still needed. SUMMARY: Despite recent innovations in antipsychotics, many schizophrenia patients continue to suffer from treatment-resistant AVH and social dysfunctions. Recent studies suggested that real-time NFB shows promise in enabling patients to gain control over AVH by regulating their own speech-related/language-related networks. Although fMRI-NFB is suitable for regulating localized activity, EEG/MEG-NFB are ideal for regulating the ever-changing AVH. Although there are still many challenges including logistic complexity and burden on patients, we hope that such innovative real-time NFB trainings will help patients to alleviate severe symptoms and improve social functioning.

The prognostic impact of skeletal muscle status and bone mineral density for resected distal cholangiocarcinoma.

BACKGROUND & AIMS: The preoperative body composition and bone mineral density (BMD) have been reported as prognostic factors for several cancers. However, the prognostic impact of the preoperative body composition and BMD for resected distal cholangiocarcinoma (DCC) remains unclear. METHODS: A total of 111 patients who underwent pancreatoduodenectomy for DCC between 2002 and 2017 were analyzed. The skeletal muscle index (SMI) and BMD were measured by preoperative computed tomography. The optimal cut-off value of the body composition and BMD were selected based on the minimum P-value obtained by the log-rank test. The prognostic significance of the preoperative body composition and BMD was investigated using multivariate analysis. RESULTS: The median values of the SMI (45.7 vs. 36.7 cm2/m2, P < 0.001) and BMD (128.5 vs. 101.0 Hounsfield units [HU], P = 0.005) in male and female were significantly different. The optimal cut-off values for the SMI were 55 cm2/m2 in male and 36 cm2/m2 in female, and those for the BMD were 75 HU in male and 74 HU in female. A multivariate analysis identified low SMI (hazard ratio [HR], 4.340; P = 0.044), low BMD (HR, 5.333; P < 0.001) and microscopic venous invasion (HR, 2.019; P = 0.026) as independent prognostic factors for the survival. CONCLUSIONS: A preoperative low SMI and low BMD were independent prognostic factors for resected DCC.

The evaluation of the 8th and 7th edition of the American joint committee on cancer tumor classification for distal cholangiocarcinoma: the proposal of a modified new tumor classification.

BACKGROUND: The 7th and 8th editions of the American Joint Committee on Cancer (AJCC) tumor (T) classification of distal cholangiocarcinoma (DCC), which are based on either layer or depth, may not accurately stratify patient survival. METHODS: A total of 121 patients who underwent resection for DCC between 2002 and 2016 were analyzed. The impact of the AJCC staging system on survival was examined and a new T classification was established based on independent prognostic factors. RESULTS: Regarding overall survival, the optimal depth of invasion (DOI) cut-off value (8 mm) was the only independent prognostic factor. Regarding the relapse-free survival (RFS), a DOI >8 mm, portal vein (PV) invasion, and duodenal or pancreatic invasion were independent prognostic factors. A new T classification was developed as follows: T1, no invasion of adjacent organs; T2, invasion of the duodenum or pancreas; T3, invasion >8 mm into the bile duct wall; and T4, invasion of the PV or arteries. There were no significant differences in RFS according to the 8th edition of the AJCC. However, significant differences were observed in the RFS between T1 and T2 and between T2 and T3. CONCLUSION: A new T classification based on the layer and depth may be more feasible.

Neurophysiological Face Processing Deficits in Patients With Chronic Schizophrenia: An MEG Study.

BACKGROUND: Neuropsychological studies have revealed that patients with schizophrenia (SZ) have facial recognition difficulties and a reduced visual evoked N170 response to human faces. However, detailed neurophysiological evidence of this face processing deficit in SZ with a higher spatial resolution has yet to be acquired. In this study, we recorded visual evoked magnetoencephalography (MEG) and examined whether M170 (a magnetic counterpart of the N170) activity deficits are specific to faces in patients with chronic SZ. METHODS: Participants were 26 patients with SZ and 26 healthy controls (HC). The M170 responses to faces and cars were recorded from whole-head MEG, and global field power over each temporal cortex was analyzed. The distributed M170 sources were also localized using a minimum-norm estimation (MNE) method. Correlational analyses between M170 responses and demographics/symptoms were performed. RESULTS: As expected, the M170 was significantly smaller in the SZ compared with the HC group in response to faces, but not to cars (faces: p = 0.01; cars: p = 0.55). The MNE analysis demonstrated that while the M170 was localized over the fusiform face area (FFA) in the HC group, visual-related brain regions other than the FFA were strongly activated in the SZ group in both stimulus conditions. The severity of negative symptoms was negatively correlated with M170 power (rho = -0.47, p = 0.01) in SZ. Within HC, there was a significant correlation between age and the M170 responses to faces averaged for both hemispheres (rho = 0.60, p = 0.001), while such a relationship was not observed in patients with SZ (rho = 0.09, p = 0.67). CONCLUSION: The present study showed specific reductions in the M170 response to human faces in patients with SZ. Our findings could suggest that SZ is characterized by face processing deficits that are associated with the severity of negative symptoms. Thus, we suggest that social cognition impairments in SZ might, at least in part, be caused by this functional face processing deficit.

Long-Term Test-Retest Reliability of Auditory Gamma Oscillations Between Different Clinical EEG Systems.

OBJECTIVE: There is increasing interest in the utility of gamma-band activity for assessing various brain functions, including perception, language, memory, and cognition. The auditory steady-state response (ASSR) involves neural activity in the brain elicited by trains of a click sound, and its maximum response is obtained at 40 Hz (40-Hz ASSR). Abnormalities of the 40-Hz ASSR are also widely reported in patients with schizophrenia. Thus, the test-retest reliability of the ASSR is important for its clinical and translational application. However, there are only limited studies reporting the short-term reliability between acquisitions at two time points made using the same electroencephalogram (EEG) system. Furthermore, the long-term reliability between multiple EEG systems and the reliability of spontaneous gamma activity are unknown but are crucial for multicenter collaborative research. METHODS: We examined the long-term test-retest reliability of 40-Hz ASSR oscillatory activities indexed by the phase locking factor (PLF), evoked power, and (non-phase-locked) induced power between two clinical 19-electrode EEG systems [recorded twice for EEG-1 (time1 and time2) and EEG-2 (time3 and time4)] at four time points from 14 healthy controls over a duration of 5 months. Test-retest reliability was examined using intraclass correlation coefficients (ICCs). RESULTS: Both PLF and evoked power showed good to excellent ICCs (>0.60), mainly in the Fz-electrode, both within each EEG system-EEG-1 [(time1 vs. time2) PLF: ICC = 0.66, evoked power: ICC = 0.88] and EEG-2 [(time3 vs. time4) PLF: ICC = 0.82, evoked power: ICC = 0.77]-and between the two EEG systems [(EEG-1 vs. EEG-2) PLF: ICC = 0.73, evoked power: ICC = 0.84]. In contrast, induced power showed the highest (excellent) ICC between the two EEG systems (ICC = 0.95) mainly in the Cz-electrode. For PLF, the Fz-electrode showed better test-retest reliability across all EEG recordings than the Cz-electrode (Fz: ICC = 0.67, Cz: ICC = 0.63), whereas we found similar excellent reproducibility across all EEG recordings from both electrodes for evoked power (Fz: ICC = 0.79, Cz: ICC = 0.77) and induced power (Fz: ICC = 0.79, Cz: ICC = 0.80). CONCLUSION: The 40-Hz ASSR oscillatory activities, including induced power, showed excellent test-retest reliability, even when using different EEG systems over a duration of 5 months. These findings confirm the utility of the 40-Hz ASSR as a reliable clinical and translatable biomarker for multicenter collaborative research.

Ligand-based Activity Cliff Prediction Models with Applicability Domain.

Activity cliffs (ACs) are formed by pairs of structurally similar compounds with large differences in potency. Predicting ACs is of high interest in lead optimization for drug discovery. Previous AC prediction models that focused on matched molecular pair (MMP) cliffs produced adequate performances. However, the extrapolation ability of these models is unclear because the main scaffold for MMPs, the core structure, could exist in both training and test data sets. Also, representation of MMPs did not consider the attachment points where the core and R-group substituents are connected. In this study, we aimed to improve a ligand-based AC prediction method using molecular fingerprints. We incorporated applicability domain, which was defined using R-path fingerprints to consider the local environment around an attachment point. Rigorous evaluation of the extrapolation ability of AC prediction models showed that MMP-cliffs were accurately predicted for nine biological targets. Furthermore, incorporation of training MMPs with cores distinct from those of test MMPs improved the predictability compared with using training MMPs with only similar cores.

Brainstem and early cortical auditory activities associated with language differences in acoustic cue weighting for voicing perception.

The purpose of the present study was to identify neural activities reflecting language differences in acoustic cue weighting for phonetic perception. We examined whether brainstem and early cortical auditory responses to voice-onset time (VOT) and onset frequency of fundamental frequency (onset F0) were different between two groups of listeners, native Japanese speakers and Korean second-language learners of Japanese, who use a VOT and onset F0, respectively, as the primary perceptual cue for voicing. In the experiment, we measured auditory brainstem responses (ABRs) and cortical N1 response of the Japanese and Korean participants while listening to stop-consonant stimuli varying in VOT and onset F0 (10 ms and 80 Hz, 30 ms and 80 Hz, or 30 ms and 120 Hz). We found that the N1 response was much more sensitive to VOT distinction in the Japanese than Korean participants, although the distinction of onset F0 was not reflected in early cortical responses in either language groups. There was no obvious difference in the ABRs between the Japanese and Korean participants. These results suggest that early cortical auditory activity is related to the processing of acoustic cue weighting for phonetic perception, while brainstem auditory activity is stimulus-dependent.