Ribosylation Rapidly Induces α-Synuclein to Form Highly Cytotoxic Molten Globules of Advanced Glycation End Products

BACKGROUND: Alpha synuclein (alpha-Syn) is the main component of Lewy bodies which are associated with several neurodegenerative diseases such as Parkinson's disease. While the glycation with D-glucose that results in alpha-Syn misfold and aggregation has been studied, the effects of glycation with D-ribose on alpha-Syn have not been investigated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that ribosylation induces alpha-Syn misfolding and generates advanced glycation end products (AGEs) which form protein molten globules with high cytotoxcity. Results from native- and SDS-PAGE showed that D-ribose reacted rapidly with alpha-Syn, leading to dimerization and polymerization. Trypsin digestion and sequencing analysis revealed that during ribosylation the lysinyl residues (K(58), K(60), K(80), K(96), K(97) and K(102)) in the C-terminal region reacted more quickly with D-ribose than those of the N-terminal region. Using Western blotting, AGEs resulting from the glycation of alpha-Syn were observed within 24 h in the presence of D-ribose, but were not observed in the presence of D-glucose. Changes in fluorescence at 410 nm demonstrated again that AGEs were formed during early ribosylation. Changes in the secondary structure of ribosylated alpha-Syn were not clearly detected by CD spectrometry in studies on protein conformation. However, intrinsic fluorescence at 310 nm decreased markedly in the presence of D-ribose. Observations with atomic force microscopy showed that the surface morphology of glycated alpha-Syn looked like globular aggregates. thioflavin T (ThT) fluorescence increased during alpha-Syn incubation regardless of ribosylation. As incubation time increased, ribosylation of alpha-Syn resulted in a blue-shift (approximately 100 nm) in the fluorescence of ANS. The light scattering intensity of ribosylated alpha-Syn was not markedly different from native alpha-Syn, suggesting that ribosylated alpha-Syn is present as molten protein globules. Ribosylated products had a high cytotoxicity to SH-SY5Y cells, leading to LDH release and increase in the levels of reactive oxygen species (ROS). CONCLUSIONS/SIGNIFICANCE: alpha-Syn is rapidly glycated in the presence of D-ribose generating molten globule-like aggregations which cause cell oxidative stress and result in high cytotoxicity

Testing Hateful Speeches against Policies

In the recent years, many software systems have adopted AI techniques, especially deep learning techniques. Due to their black-box nature, AI-based systems brought challenges to traceability, because AI system behaviors are based on models and data, whereas the requirements or policies are rules in the form of natural or programming language. To the best of our knowledge, there is a limited amount of studies on how AI and deep neural network-based systems behave against rule-based requirements/policies. This experience paper examines deep neural network behaviors against rule-based requirements described in natural language policies. In particular, we focus on a case study to check AI-based content moderation software against content moderation policies. First, using crowdsourcing, we collect natural language test cases which match each moderation policy, we name this dataset HateModerate; second, using the test cases in HateModerate, we test the failure rates of state-of-the-art hate speech detection software, and we find that these models have high failure rates for certain policies; finally, since manual labeling is costly, we further proposed an automated approach to augument HateModerate by finetuning OpenAI's large language models to automatically match new examples to policies. The dataset and code of this work can be found on our anonymous website: \url{https://sites.google.com/view/content-moderation-project}

High-Dielectric PVP@PANI/PDMS Composites Fabricated via an Electric Field-Assisted Approach

Polymer-based composite films with multiple properties, such as low dielectric loss tangent, high dielectric constant, and low cost are promising materials in the area of electronics and electric industries. In this study, flexible dielectric films were fabricated via an electric field-assisted method. Polyaniline (PANI) was modified by polyvinylpyrrolidone (PVP) to form a core–shell structure to serve as functional particles and silicone rubber polydimethylsiloxane (PDMS) served as the matrix. The dielectric constant of the composites prepared under electric fields was improved by the micro-structures formed by external electric fields. With the addition of 2.5 wt% PVP@PANI, the dielectric constant could be significantly enhanced, up to 23; the dielectric loss tangent is only 1, which is lower than that of the aligned PANI samples. This new processing technology provides important insights for aligning fillers in polymer matrix to form composites with enhanced dielectric properties

An Ultrasonic-Based Radiomics Nomogram for Distinguishing Between Benign and Malignant Solid Renal Masses

ObjectivesThis study was conducted in order to develop and validate an ultrasonic-based radiomics nomogram for diagnosing solid renal masses.MethodsSix hundred renal solid masses with benign renal lesions (n = 204) and malignant renal tumors (n = 396) were divided into a training set (n = 480) and a validation set (n = 120). Radiomics features were extracted from ultrasound (US) images preoperatively and then a radiomics score (RadScore) was calculated. By integrating the RadScore and independent clinical factors, a radiomics nomogram was constructed. The diagnostic performance of junior physician, senior physician, RadScore, and radiomics nomogram in identifying benign from malignant solid renal masses was evaluated based on the area under the receiver operating characteristic curve (ROC) in both the training and validation sets. The clinical usefulness of the nomogram was assessed using decision curve analysis (DCA).ResultsThe radiomics signature model showed satisfactory discrimination in the training set [area under the ROC (AUC), 0.887; 95% confidence interval (CI), 0.860–0.915] and the validation set (AUC, 0.874; 95% CI, 0.816–0.932). The radiomics nomogram also demonstrated good calibration and discrimination in the training set (AUC, 0.911; 95% CI, 0.886–0.936) and the validation set (AUC, 0.861; 95% CI, 0.802–0.921). In addition, the radiomics nomogram model showed higher accuracy in discriminating benign and malignant renal masses compared with the evaluations by junior physician (DeLong p = 0.004), and the model also showed significantly higher specificity than the senior and junior physicians (0.93 vs. 0.57 vs. 0.46).ConclusionsThe ultrasonic-based radiomics nomogram shows favorable predictive efficacy in differentiating solid renal masses

Characteristics of spontaneous nystagmus and its correlation to video head impulse test findings in vestibular neuritis

ObjectiveTo explore the direction and SPV (slow phase velocity) of the components of spontaneous nystagmus (SN) in patients with vestibular neuritis (VN) and the correlation between SN components and affected semicircular canals (SCCs). Additionally, we aimed to elucidate the role of directional features of peripheral SN in diagnosing acute vestibular syndrome.Materials and methodsA retrospective analysis was conducted on 38 patients diagnosed with VN in our hospital between 2022 and 2023. The direction and SPV of SN components recorded with three-dimensional videonystagmography (3D-VNG) and the video head impulse test (vHIT) gain of each SCC were analyzed as observational indicators. We examined the correlation between superior and inferior vestibular nerve damage and the direction and SPV of SN components, and vHIT gain values in VN patients.ResultsThe median illness duration of between symptom onset and moment of testing was 6 days among the 38 VN patients (17 right VN and 21 left VN). In total, 31 patients had superior vestibular neuritis (SVN), and 7 had total vestibular neuritis (TVN). Among the 38 VN patients, all had horizontal component with an SPV of (7.66 ± 5.37) °/s, 25 (65.8%) had vertical upward component with a SPV of (2.64 ± 1.63) °/s, and 26 (68.4%) had torsional component with a SPV of (4.40 ± 3.12) °/s. The vHIT results in the 38 VN patients showed that the angular vestibulo-ocular reflex (aVOR) gain of the anterior (A), lateral (L), and posterior (P) SCCs on the ipsilesional side were 0.60 ± 0.23, 0.44 ± 0.15 and 0.89 ± 0.19, respectively, while the gains on the opposite side were 0.95 ± 0.14, 0.91 ± 0.08, and 0.96 ± 0.11, respectively. There was a statistically significant difference in the aVOR gain between the A-, L-SCC on the ipsilesional side and the other SCCs (p < 0.001). The aVOR gains of A-, L-, and P-SCC on the ipsilesional sides in 31 SVN patients were 0.62 ± 0.24, 0.45 ± 0.16, and 0.96 ± 0.10, while the aVOR gains on the opposite side were 0.96 ± 0.13, 0.91 ± 0.06, and 0.98 ± 0.11, respectively. There was a statistically significant difference in the aVOR gain between the A-, L-SCC on the ipsilesional side and the other SCCs (p < 0.001). In 7 TVN patients, the aVOR gains of A-, L-, and P-SCC on the ipsilesional side were 0.50 ± 0.14, 0.38 ± 0.06, and 0.53 ± 0.07, while the aVOR gains on the opposite side were 0.93 ± 0.17, 0.90 ± 0.16, and 0.89 ± 0.09, respectively. There was a statistically significant difference in the aVOR gain between the A-, L-, and P-SCC on the ipsilesional side and the other SCCs (p < 0.001). The aVOR gain asymmetry of L-SCCs in 38 VN was 36.3%. The aVOR gain asymmetry between bilateral A-SCCs and bilateral P-SCCs for VN patients with and without a vertical upward component was 12.8% and 8.3%, which was statistically significant (p < 0.05). For VN patients with and without a torsional component, the aVOR gain asymmetry of bilateral vertical SCCs was 17.0% and 6.6%, which was statistically significant (p < 0.01). Further analysis revealed a significant positive correlation between the aVOR gain asymmetry of L-SCCs and the SPV of the horizontal component of SN in all VN patients (r = 0.484, p < 0.01), as well as between the asymmetry of bilateral vertical SCCs and the SPV of torsional component in 26 VN patients (r = 0.445, p < 0.05). However, there was no significant correlation between the aVOR gains asymmetry of bilateral A-SCCs and P-SCCs and the SPV of the vertical component in 25 VN patients.ConclusionThere is a correlation between the three-dimensional direction and SPV characteristics of SN and the aVOR gain of vHIT in VN patients. These direction characteristics can help assess different SCCs impairments in patients with unilateral vestibular diseases

When a friend in Twitter is a friend in life

Twitter is a fast-growing online social network service (SNS) where users can “follow ” any other user to re-ceive his or her mini-blogs which are called “tweets”. In this paper, we study the problem of identifying a user’s off-line real-life social community, which we call the user’s Twitter off-line community, purely from ex-amining Twitter network structure. Based on obser-vations from our user-verified Twitter data and results from previous works, we propose three principles about Twitter off-line communities. Incorporating these prin-ciples, we develop a novel algorithm to iteratively dis-cover the Twitter off-line community based on a new way of measuring user closeness. According to ground truth provided by real Twitter users, our results demon-strate the effectiveness of our approach with both high precision and recall in most cases

Ginkgolide B Inhibits JAM-A, Cx43, and VE-Cadherin Expression and Reduces Monocyte Transmigration in Oxidized LDL-Stimulated Human Umbilical Vein Endothelial Cells

Aim. To investigate the effect of ginkgolide B on junction proteins and the reduction of monocyte migration in oxidized low-density lipoprotein- (ox-LDL-) treated endothelial cells. Methods. Human umbilical vein endothelial cells (HUVECs) were used in the present study. Immunofluorescence and Western blot were performed to determine the expression of junctional adhesion molecule-A (JAM-A), connexin 43 (Cx43), and vascular endothelial cadherin (VE-cadherin). Monocyte migration was detected by the Transwell assay. Results. ox-LDL stimulation increased JAM-A expression by 35%, Cx43 expression by 24%, and VE-cadherin expression by 37% in HUVECs. Ginkgolide B (0.2, 0.4, and 0.6 mg/mL) dose-dependently abolished the expression of these junction proteins. The monocyte transmigration experiments showed that the level of monocyte migration was sixfold higher in the ox-LDL-treated group than in the control group. Ginkgolide B (0.6 mg/mL) nearly completely abolished monocyte migration. Both ginkgolide B and LY294002 suppressed Akt phosphorylation and the expression of these junction proteins in ox-LDL-treated endothelial cells. These results suggest that the ginkgolide B-induced inhibition of junction protein expression is associated with blockade of the PI3K/Akt pathway. Conclusion. Ginkgolide B suppressed junction protein expression and reduced monocyte transmigration that was induced by ox-LDL. Ginkgolide B may improve vascular permeability in atherosclerosis