Optimizing motor-timing decision via adaptive risk-return control

Human’s ability of optimal motor-timing decision remains debated. The optimality seems context-dependent as the sub-optimality was often observed for tasks with different gain/loss configurations: people achieved optimality with symmetric gain configuration but not with asymmetric configuration. In the current study, we designed a temporal decision-making task where participants could adjust the sensitivity parameter (i.e., risk-return trade-off) of the gain function, in order to testify whether people could optimize the responses for asymmetric gain configuration by adjusting the sensitivity parameter. Participants were asked to click a point within a certain spatial region at a specified timing, where the click timing determined the reward whilst the click position determined the sensitivity parameter. We prepared three types of gain functions (symmetric, risk-after and risk-before conditions) and tested whether or not the participants achieved Bayesian optimality irrespective of gain structure. Most participants’ performance reached optimality not only in the symmetric condition but also in the asymmetric condition, albeit some discrepancies from optimality observed in the risk-before condition. This confirmed that people could achieve Bayesian optimality even for asymmetric gain configuration. We argued that the adaptive risk-return is beneficial for the performance optimality

Fear of eyes: triadic relation among social anxiety, trypophobia, and discomfort for eye cluster

Imagine you are being gazed at by multiple individuals simultaneously. Is the provoked anxiety a learned social-specific response or related to a pathological disorder known as trypophobia? A previous study revealed that spectral properties of images induced aversive reactions in observers with trypophobia. However, it is not clear whether individual differences such as social anxiety traits are related to the discomfort associated with trypophobic images. To investigate this issue, we conducted two experiments with social anxiety and trypophobia and images of eyes and faces. In Experiment 1, participants completed a social anxiety scale and trypophobia questionnaire before evaluation of the discomfort experienced upon exposure to pictures of eye. The results showed that social anxiety had a significant indirect effect on the discomfort associated with the eye clusters, and that the effect was mediated by trypophobia. Experiment 2 replicated Experiment 1 using images of human face. The results showed that, as in Experiment 1, a significant mediation effect of trypophobia was obtained, although the relationship between social anxiety and the discomfort rating was stronger than in Experiment 1. Our findings suggest that both social anxiety and trypophobia contribute to the induction of discomfort when one is gazed at by many people

Fingerprinting Evaluation and Gut Microbiota Regulation of Polysaccharides from Jujube (<i>Ziziphus jujuba</i> Mill.) Fruit

Jujube fruit was well-loved and praised by the broad masses due to its delicious taste, abundant nutritional value, and medicinal properties. Few studies reported the quality evaluation and gut microbiota regulation effect of polysaccharides of jujube fruits from different producing areas. In the present study, multi-level fingerprint profiling, including polysaccharides, oligosaccharides, and monosaccharides, was established for the quality evaluation of polysaccharides from jujube fruits. For polysaccharides, the total content in jujube fruits ranged from 1.31% to 2.22%, and the molecular weight distribution (MWD) ranged from 1.14 × 105 to 1.73 × 106 Da. The MWD fingerprint profiling of polysaccharides from eight producing areas was similar, but the profile of infrared spectroscopy (IR) showed differentiation. The characteristic signals were screened and used to establish a discrimination model for the identification of jujube fruits from different areas, and the accuracy of identification reached 100.00%. For oligosaccharides, the main components were galacturonic acid polymers (DP, 2–4), and the profile of oligosaccharides exhibited high similarity. The monosaccharides, GalA, Glc, and Ara, were the primary monosaccharides. Although the fingerprint of monosaccharides was semblable, the composing proportion of monosaccharides revealed significant differences. In addition, the polysaccharides of jujube fruits could regulate the gut microbiota composition and possess potential therapeutic effects on dysentery and nervous system diseases

Cortical Morphometric Vulnerability to Generalized Epilepsy Reflects Chromosome- and Cell Type-specific Transcriptomic Signatures.

AimsGeneralized epilepsy is thought to involve distributed brain networks. However, the molecular and cellular factors that render different brain regions more vulnerable to epileptogenesis remain largely unknown. We aimed to investigate epilepsy-related morphometric similarity network (MSN) abnormalities at the macroscale level and their relationships with microscale gene expressions at the microscale level.MethodsWe compared the MSN of genetic generalized epilepsy with generalized tonic-clonic seizures patients (GGE-GTCS, n = 101) to demographically-matched healthy controls (HC, n = 150). Cortical MSNs were estimated by combining seven morphometric features derived from structural magnetic resonance imaging for each individual. Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen Human Brain Atlas.ResultsGGE-GTCS patients exhibited decreased regional MSNs in primary motor, prefrontal, and temporal regions, and increases in occipital, insular, and posterior cingulate cortices, when compared to the HC. These case-control neuroimaging differences were validated using split-half analyses and were not affected by medication or drug response effects. When assessing associations with gene expression, genes associated with GGE-GTCS-related MSN differences were enriched in several biological processes, including "synapse organization", "neurotransmitter transport" pathways, and excitatory/inhibitory neuronal cell types. Collectively, the GGE-GTCS-related cortical vulnerabilities were associated with chromosomes 4, 5, 11, and 16, and were dispersed bottom-up at the cellular, pathway, and disease levels, which contributed to epileptogenesis, suggesting diverse neurobiologically relevant enrichments in GGE-GTCS.ConclusionsBy bridging the gaps between transcriptional signatures and in vivo neuroimaging, we highlighted the importance of using MSN abnormalities of the human brain in GGE-GTCS patients to investigate disease-relevant genes and biological processes

Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases

Bruton’s tyrosine kinase (BTK) is an attractive target in inflammatory and autoimmune diseases. However, the effectiveness of BTK inhibitors is limited by side effects and drug resistance. In this study, we report the development of novel BTK proteolysis targeting chimeras (PROTACs) with different classes of BTK-targeting ligands (e.g., spebrutinib) other than ibrutinib. Compound 23 was identified as a potent and fast BTK PROTAC degrader, exhibiting outstanding degradation potency and efficiency in Mino cells (DC50, 4 h = 1.29 ± 0.3 nM, t1/2, 20 nM = 0.59 ± 0.20 h). Furthermore, compound 23 forms a stable ternary complex, as confirmed by the HTRF assay. Notably, 23 down-regulated the BTK-PLCγ2-Ca2+-NFATc1 signaling pathway activated by RANKL, thus inhibiting osteo­clasto­genesis and attenuating alveolar bone resorption in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related inflammatory diseases, expanding the potential of BTK PROTACs

Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases

Bruton’s tyrosine kinase (BTK) is an attractive target in inflammatory and autoimmune diseases. However, the effectiveness of BTK inhibitors is limited by side effects and drug resistance. In this study, we report the development of novel BTK proteolysis targeting chimeras (PROTACs) with different classes of BTK-targeting ligands (e.g., spebrutinib) other than ibrutinib. Compound 23 was identified as a potent and fast BTK PROTAC degrader, exhibiting outstanding degradation potency and efficiency in Mino cells (DC50, 4 h = 1.29 ± 0.3 nM, t1/2, 20 nM = 0.59 ± 0.20 h). Furthermore, compound 23 forms a stable ternary complex, as confirmed by the HTRF assay. Notably, 23 down-regulated the BTK-PLCγ2-Ca2+-NFATc1 signaling pathway activated by RANKL, thus inhibiting osteo­clasto­genesis and attenuating alveolar bone resorption in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related inflammatory diseases, expanding the potential of BTK PROTACs