Liver X Receptor Ligand GAC0001E5 Downregulates Antioxidant Capacity and ERBB2/HER2 Expression in HER2-Positive Breast Cancer Cells.

The HER2-positive subtype accounts for approximately one-fifth of all breast cancers. Insensitivity and development of acquired resistance to targeted therapies in some patients contribute to their poor prognosis. HER2 overexpression is associated with metabolic reprogramming, facilitating cancer cell growth and survival. Novel liver X receptor (LXR) ligand GAC0001E5 (1E5) has been shown to inhibit cancer cell proliferation by disrupting glutaminolysis and inducing oxidative stress. In this study, HER2-positive breast cancer cells were treated with 1E5 to determine their potential inhibitory effects and mechanisms of action in HER2-positive breast cancers. Similar to previous observations in other cancer types, 1E5 treatments inhibited LXR activity, expression, and cancer cell proliferation. Expression of fatty acid synthesis genes, including fatty acid synthase (FASN), was downregulated following 1E5 treatment, and results from co-treatment experiments with an FASN inhibitor suggest that the same pathway is targeted by 1E5. Treatments with 1E5 disrupted glutaminolysis and resulted in increased oxidative stress. Strikingly, HER2 transcript and protein levels were both significantly downregulated by 1E5. Taken together, these findings indicate the therapeutic potential of targeting HER2 overexpression and associated metabolic reprogramming via the modulation of LXR in HER2-positive breast cancers.

Medication Usage Record-Based Predictive Modeling of Neurodevelopmental Abnormality in Infants under One Year: A Prospective Birth Cohort Study.

Early identification of children with neurodevelopmental abnormality is a major challenge, which is crucial for improving symptoms and preventing further decline in children with neurodevelopmental abnormality. This study focuses on developing a predictive model with maternal sociodemographic, behavioral, and medication-usage information during pregnancy to identify infants with abnormal neurodevelopment before the age of one. In addition, an interpretable machine-learning approach was utilized to assess the importance of the variables in the model. In this study, artificial neural network models were developed for the neurodevelopment of five areas of infants during the first year of life and achieved good predictive efficacy in the areas of fine motor and problem solving, with median AUC = 0.670 (IQR: 0.594, 0.764) and median AUC = 0.643 (IQR: 0.550, 0.731), respectively. The final model for neurodevelopmental abnormalities in any energy region of one-year-old children also achieved good prediction performance. The sensitivity is 0.700 (IQR: 0.597, 0.797), the AUC is 0.821 (IQR: 0.716, 0.833), the accuracy is 0.721 (IQR: 0.696, 0.739), and the specificity is 0.742 (IQR: 0.680, 0.748). In addition, interpretable machine-learning methods suggest that maternal exposure to drugs such as acetaminophen, ferrous succinate, and midazolam during pregnancy affects the development of specific areas of the offspring during the first year of life. This study established predictive models of neurodevelopmental abnormality in infants under one year and underscored the prediction value of medication exposure during pregnancy for the neurodevelopmental outcomes of the offspring.

Toward More Selective Antibiotic Inhibitors: A Structural View of the Complexed Binding Pocket of E. coli Peptide Deformylase.

Peptide deformylase (PDF) is involved in bacterial protein maturation processes. Originating from the interest in a new antibiotic, tremendous effort was put into the refinement of PDF inhibitors (PDFIs) and their selectivity. We obtained a full NMR backbone assignment the emergent additional protein backbone resonances of ecPDF 1-147 in complex with 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide (2), a potential new structural scaffold for more selective PDFIs. We also determined the complex crystal structures of E. coli PDF (ecPDF fl) and 2. Our structure suggests an alternative ligand conformation within the protein, a possible starting point for further selectivity optimization. The orientation of the second ligand conformation in the crystal structure points toward a small region of the S1' pocket, which differs between bacterial PDFs and human PDF. Moreover, we analyzed the binding mode of 2 via NMR TITAN line shape analysis, revealing an induced fit mechanism.

Super High Contrast USPIO-Enhanced Cerebrovascular Angiography Using Ultrashort Time-to-Echo MRI.

Background: Ferumoxytol (Ferahame, AMAG Pharmaceuticals, Waltham, MA) is increasingly used off-label as an MR contrast agent due to its relaxivity and safety profiles. However, its potent T2∗ relaxivity limits achievable T1-weighted positive contrast and leads to artifacts in standard MRI protocols. Optimization of protocols for ferumoxytol deployment is necessary to realize its potential. Methods: We present first-in-human clinical results of the Quantitative Ultrashort Time-to-Echo Contrast Enhanced (QUTE-CE) MRA technique using the superparamagnetic iron oxide nanoparticle agent ferumoxytol for vascular imaging of the head/brain in 15 subjects at 3.0T. The QUTE-CE MRA method was implemented on a 3T scanner using a stack-of-spirals 3D Ultrashort Time-to-Echo sequence. Time-of-flight MRA and standard TE T1-weighted (T1w) images were also collected. For comparison, gadolinium-enhanced blood pool phase images were obtained retrospectively from clinical practice. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and intraluminal signal heterogeneity (ISH) were assessed and compared across approaches with Welch's two-sided t-test. Results: Fifteen volunteers (54 ± 17 years old, 9 women) participated. QUTE-CE MRA provided high-contrast snapshots of the arterial and venous networks with lower intraluminal heterogeneity. QUTE-CE demonstrated significantly higher SNR (1707 ± 226), blood-tissue CNR (1447 ± 189), and lower ISH (0.091 ± 0.031) compared to ferumoxytol T1-weighted (551 ± 171; 319 ± 144; 0.186 ± 0.066, respectively) and time-of-flight (343 ± 104; 269 ± 82; 0.190 ± 0.016, respectively), with p < 0.001 in each comparison. The high CNR increased the depth of vessel visualization. Vessel lumina were captured with lower heterogeneity. Conclusion: Quantitative Ultrashort Time-to-Echo Contrast-Enhanced MR angiography provides approximately 5-fold superior contrast with fewer artifacts compared to other contrast-enhanced vascular imaging techniques using ferumoxytol or gadolinium, and to noncontrast time-of-flight MR angiography, for clinical vascular imaging. This trial is registered with NCT03266848.

Exploring relevant factors of cognitive impairment in the elderly Chinese population using Lasso regression and Bayesian networks.

Older adults are highly susceptible to developing cognitive impairment(CI). Various factors contribute to the prevalence of CI, but the potential relationships among these factors remain unclear. This study aims to explore the relevant factors associated with CI in Chinese older adults and analyze the potential relationships between CI and these factors.We analyzed the data on 6886 older adults aged≥60 from the China Health and Retirement Longitudinal Study (CHARLS) 2018. Lasso regression was initially used to screening variables. Bayesian Networks(BNs) were used to identify the correlates of CI and potential associations between factors. After screening with Lasso regression, 11 variables were finally included in the BNs. The BNs, by establishing a complex network relationship, revealed that age, education, and indoor air pollution were the direct correlates affecting the occurrence of CI in older adults. It also indicated that marital status indirectly influenced CI through age, and residence indirectly linked to CI through two pathways: indoor air pollution and education.Our findings underscore the effectiveness of BNs in unveiling the intricate network linkages among CI and its associated factors, holding promising applications. It can serve as a reference for public health departments to address the prevention of CI in the elderly.

A Time-Consistency Curriculum for Learning from Instance-Dependent Noisy Labels.

Many machine learning algorithms are known to be fragile on simple instance-independent noisy labels. However, noisy labels in real-world data are more devastating since they are produced by more complicated mechanisms in an instance-dependent manner. In this paper, we target this practical challenge of Instance-Dependent Noisy Labels by jointly training (1) a model reversely engineering the noise generating mechanism, which produces an instance-dependent mapping between the clean label posterior and the observed noisy label; and (2) a robust classifier that produces clean label posteriors. Compared to previous methods, the former model is novel and enables end-to-end learning of the latter directly from noisy labels. An extensive empirical study indicates that the time-consistency of data is critical to the success of training both models and motivates us to develop a curriculum selecting training data based on their dynamics on the two models' outputs over the course of training. We show that the curriculum-selected data provide both clean labels and high-quality input-output pairs for training the two models. Therefore, it leads to promising and robust classification performance even in notably challenging settings of instance-dependent noisy labels where many SoTA methods could easily fail. Extensive experimental comparisons and ablation studies further demonstrate the advantages and significance of the time-consistency curriculum in learning from instance-dependent noisy labels on multiple benchmark datasets.

Structural Insights into Antibacterial Payload Release from Gold Nanoparticles Bound to E. coli Peptide Deformylase.

The lack of new antibiotics and the rapidly rising number of pathogens resistant to antibiotics pose a serious problem to mankind. In bacteria, the cell membrane provides the first line of defence to antibiotics by preventing them from reaching their molecular target. To overcome this entrance barrier, it has been suggested[1] that small Gold-Nanoparticles (AuNP) could possibly function as drug delivery systems for antibiotic ligands. Using actinonin-based ligands, we provide here proof-of-principle of AuNP functionalisation, the capability to bind and inhibit the target protein of the ligand, and the possibility to selectively release the antimicrobial payload. To this end, we successfully synthesised AuNP coated with thio-functionalised actinonin and a derivative. Interactions between 15N-enriched His-peptide deformylase 1-147 from E. coli (His-ecPDF 1-147) and compound-coated AuNP were investigated via 2D 1H-15N-HSQC NMR spectra proving the direct binding to His-ecPDF 1-147. More importantly by adding dithiothreitol (DTT), we show that the derivative is successfully released from AuNPs while still bound to His-ecPDF 1-147. Our findings indicate that AuNP-conjugated ligands can address and bind intracellular target proteins. The system introduced here presents a new delivery platform for antibiotics and allows for the easy optimisation of ligand coated AuNPs.

False Correlation Reduction for Offline Reinforcement Learning.

Offline reinforcement learning (RL) harnesses the power of massive datasets for resolving sequential decision problems. Most existing papers only discuss defending against out-of-distribution (OOD) actions while we investigate a broader issue, the false correlations between epistemic uncertainty and decision-making, an essential factor that causes suboptimality. In this paper, we propose falSe COrrelation REduction (SCORE) for offline RL, a practically effective and theoretically provable algorithm. We empirically show that SCORE achieves the SoTA performance with 3.1x acceleration on various tasks in a standard benchmark (D4RL). The proposed algorithm introduces an annealing behavior cloning regularizer to help produce a high-quality estimation of uncertainty which is critical for eliminating false correlations from suboptimality. Theoretically, we justify the rationality of the proposed method and prove its convergence to the optimal policy with a sublinear rate under mild assumptions.

Super-tough poly(lactic acid)/silicone rubber thermoplastic vulcanizates: The organic and inorganic synergistic interfacial compatibilization.

Polymer modification using silicone rubber represents a promising avenue for enhancing physico-mechanical properties. However, achieving optimal performance through direct blending is hindered by the poor interface compatibility between silicone rubber and the matrix. In this study, we prepared super-tough thermoplastic vulcanizates (TPVs) of polylactic acid/silicone rubber through dynamic vulcanization with PLA, methyl vinyl silicone rubber (MVQ), glycidyl methacrylate grafted MVQ (MVQ-g-GMA), and fumed silica nanoparticles (SiO2). The impact of the SiO2 addition in MVQ on the morphology, mechanical properties, crystallization, and thermal properties of the TPVs was investigated. The results showed that MVQ-g-GMA and SiO2 exhibited a synergistic compatibilization effect significantly improving the interfacial adhesion between PLA and MVQ. Therefore, the impact and tensile strength of the TPVs increased from 8.0 kJ/m2 and 22.2 MPa to 62.6 kJ/m2 and 36.7 MPa, respectively. Moreover, the TPVs also presented good low-temperature toughness with a maximum impact strength of 40.4 kJ/m2 at -20 °C. Additionally, improvements in thermal stability and crystallization rate were also observed. Overall, combining organic and inorganic synergistic compatibilization is a feasible and effective method to fabricate outstanding low-temperature toughness to PLA.

Monkeypox Virus Crosstalk with HIV: An Integrated Skin Transcriptome and Machine Learning Study.

The emergence of the monkeypox virus (MPXV) outbreak presents a formidable challenge to human health. Emerging evidence suggests that individuals with HIV have been disproportionately affected by MPXV, with adverse clinical outcomes and higher mortality rates. However, the shared molecular mechanisms underlying MPXV and HIV remain elusive. We identified differentially expressed genes (DEGs) from two public data sets, GSE219036 and GSE184320, and extracted common DEGs between MPXV and HIV. We further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interactions (PPI), candidate drug assessment, and immune correlation of hub genes analysis. We validated the key biomarkers using multiple machine learning (ML) methods including random forest (RF), t-distributed stochastic neighbor embedding (tSNE), and uniform manifold approximation and projection (UMAP). A total of 59 common DEGs were identified between MPXV and HIV. Our functional analysis highlighted multiple pathways, including the ERK cascade, NF-κB signaling, and various immune responses, playing a collaborative role in the progression of both diseases. The PPI and gene co-expression networks were constructed, and five key genes with significant immune correlations were identified and validated by multiple ML models, including SPRED1, SPHK1, ATF3, AKT3, and AKT1S1. Our study emphasizes the common pathogenesis of HIV and MPXV and highlights the pivotal genes and shared pathways, providing new opportunities for evidence-based management strategies in HIV patients co-infected with MPXV.

Genetic evidence implicating circulating lipids and lipid drug targets in pterygium.

There is limited knowledge about the impact of circulating lipids and lipid-modifying drugs on pterygium development, with conflicting results reported. Our study aimed to address these questions by applying the Mendelian randomization (MR) approach. A two-step MR model was developed. In the first step, bidirectional two-sample MR was employed to establish the causal relationship between circulating lipids and pterygium risk. In the second step, drug-target MR analysis was conducted to assess the causal effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors on pterygium outcomes. Genetically predicted low-density lipoprotein cholesterol (LDL-c) levels were found to be significantly associated with an increased risk of pterygium (Inverse variance weighted [IVW] odds ratio [OR] = 2.227; P = 1.53 × 10-4). Similarly, higher total cholesterol (TC) levels exhibited a suggestive association with greater susceptibility to pterygium (IVW OR = 1.806; P = 1.70 × 10-3). Through drug-target MR, a positive causal association was noted between HMGCR-mediated LDL-c levels and pterygium (IVW OR = 6.999; P = 0.016), suggesting that statins may be effective in reducing pterygium risk. The present findings suggest that circulating TC and LDL-c are risk factors for pterygium. Additionally, the results indicate that HMGCR inhibitors, which lower LDL-c levels, have a potential protective effect on pterygium outcomes. Further research is warranted to elucidate the underlying mechanisms involved in pterygium pathogenesis, with a particular focus on cholesterol metabolism.

A Study of the Relationship between Men Who Have Sex with Men Stigma and Depression: A Moderated Mediation Model.

(1) Background: Men who have sex with men (MSM) have a high prevalence of depression due to stigma. However, whether resilience and social support play a moderating role in the effects of stigma on depression remains to be tested. This study constructed a moderated mediation model to explore the mediating role of perceived stigma in the relationship between enacted stigma and depression and whether this relationship is moderated by social support. (2) Methods: MSM were recruited during November-December 2022 using a non-probability sampling method, and a total of 1091 participants were included. Enacted stigma, perceived stigma, resilience, social support, and depressive symptoms were measured. Mediation and moderated mediation models were used to analyze the relationships between these variables. (3) Results: Moderated mediation analyses show that enacted stigma indirectly affects depression through perceived stigma (ß = 0.315, 95% confidence interval = 0.221 to 0.421). Social support had a positive moderating effect between enacted stigma and depressive symptoms (ß = 0.194, p < 0.001) and a negative moderating effect between perceived stigma and depressive symptoms (ß = -0.188, p < 0.001). (4) Resilience and perceived stigma mediated the relationship between enacted stigma and depression, and the relationship between enacted stigma, perceived stigma, and depression was moderated by social support. Reducing stigma while increasing social support has the potential to alleviate depressive symptoms among Chinese MSM.

Using oscillatory and aperiodic neural activity features for identifying idle state in SSVEP-based BCIs reduces false triggers.

Objective.In existing studies, rhythmic (oscillatory) components were used as main features to identify brain states, such as control and idle states, while non-rhythmic (aperiodic) components were ignored. Recent studies have shown that aperiodic (1/f) activity is functionally related to cognitive processes. It is not clear if aperiodic activity can distinguish brain states in asynchronous brain-computer interfaces (BCIs) to reduce false triggers. In this paper, we propose an asynchronous method based on the fusion of oscillatory and aperiodic features for steady-state visual evoked potential-based BCIs.Approach.The proposed method first evaluates the oscillatory and aperiodic components of control and idle states using irregular-resampling auto-spectral analysis. Oscillatory features are then extracted using the spectral power of fundamental, second-harmonic, and third-harmonic frequencies of the oscillatory component, and aperiodic features are extracted using the slope and intercept of the first-order polynomial of the spectral fit of the aperiodic component under a log-logarithmic axis. The process produces two types of feature pools (oscillatory, aperiodic features). Next, feature selection (dimensionality reduction) is applied to the feature pools by Bonferroni correctedp-values from two-way analysis of variance. Last, these spatial-specific statistically significant features are used as input for classification to identify the idle state.Mainresults.On a 7-target dataset from 15 subjects, the mix of oscillatory and aperiodic features achieved an average accuracy of 88.39% compared to 83.53% when using oscillatory features alone (4.86% improvement). The results demonstrated that the proposed idle state recognition method achieved enhanced performance by incorporating aperiodic features.Significance.Our results demonstrated that (1) aperiodic features were effective in recognizing idle states and (2) fusing features of oscillatory and aperiodic components enhanced classification performance by 4.86% compared to oscillatory features alone.

Gone with the weed: incidents of adolescent marijuana use in the United States, 1976-2021.

PURPOSE: This study sought to examine grouped and right-censored (GRC) counts of adolescent marijuana use and estimate its temporal trajectories and sociodemographic disparities over almost half a century. METHODS: After compiling 46 waves of nationally representative data from the Monitoring the Future (MTF) study from 1976 to 2021 (sample size = 491,348), we utilized an innovative modified Poisson (mixture) approach to analyze past-year marijuana use quantified by GRC counts. RESULTS: The overall reduction in incidence rates of marijuana use was attributable to an almost 40% reduction in the risk of marijuana use (with the proportion of at-risk adolescents at 51.36% in 1979 and 31.53% in 2021). Despite substantial changes over the study period, the recent incidence rates for at-risk individuals were similar to those in the early 1980s. Living in an intact family was a protective factor against adolescent marijuana use over time. CONCLUSIONS: The incidence rates of marijuana use among at-risk students, especially those from disadvantaged families, remained high over the study period. The modified Poisson (mixture) approach serves as the preferred tool for modeling GRC responses. It is essential to distinguish among risk, at-risk incidence, and overall incidence when assessing substance use and other risky behaviors.

[Pricking and cupping at Jianbo area combined with conventional acupuncture for scapulohumeral periarthritis of frozen stage: a randomized controlled trial].

OBJECTIVE: To compare the clinical effect of conventional acupuncture combined with pricking and cupping at Jianbo area and conventional acupuncture in the treatment of scapulohumeral periarthritis of frozen stage. METHODS: A total of 66 patients with scapulohumeral periarthritis of frozen stage were randomly divided into a combination group (31 cases) and an acupuncture group (35 cases, 1 case dropped off). Both groups were given functional exercise. Patients in the acupuncture group were treated with acupuncture at Jianyu (LI 15), Jianliao (TE 14), Binao (LI 14) and ashi point on the affected side, once every other day, three times a week, for a total of 4 weeks. On the basis of treatment in the acupuncture group, the patients in the combination group were treated with pricking and cupping at Jianbo area (the area surrounded by the 3 acupoints of Tianzong [SI 11], Naoshu [SI 10] and Jianzhen [SI 9]), once a week for 4 weeks. The University of California-Los Angeles (UCLA) shoulder joint score, visual analogue scale (VAS) score before treatment, after treatment and after 6 months of treatment completion (follow-up) and tenderness threshold before and after treatment, and the clinical effects of the two groups after treatment and in follow-up were evaluated. RESULTS: In the two groups, after treatment and in follow-up, the UCLA shoulder joint scores were higher than those before treatment (P<0.05), and the VAS scores were lower than those before treatment (P<0.05). In the combination group, after treatment and in follow-up, the UCLA shoulder joint score was higher than that of the acupuncture group (P<0.05), and the VAS score was lower than that of the acupuncture group (P<0.05). After treatment, the tenderness thresholds of the two groups were higher than those before treatment (P<0.05), and the tenderness threshold in the combination group was higher than that in the acupuncture group (P<0.05). After treatment and in follow-up, the cured and markedly effective rate of the combination group was 48.4% (15/31) and 51.6% (16/31) respectively, which was higher than 23.5% (8/34) and 23.5% (8/34) of the acupuncture group (P<0.05). CONCLUSION: Pricking and cupping in Jianbo area combined with conventional acupuncture can improve shoulder joint function and relieve shoulder joint pain in patients with scapulohumeral periarthritis of frozen stage, and the curative effect is better than that of single conventional acupuncture.

Inequities in COVID-19 vaccination coverage for adolescents with and without disability, national immunization Survey-Child COVID module, July 22, 2021-February 26, 2022.

BACKGROUND: Some people with disabilities are likely at increased risk of health impacts from coronavirus disease 2019 (COVID-19). OBJECTIVE: To describe parent-reported COVID-19 vaccination status of adolescents (aged 13-17 years) and parental intent to get their child vaccinated, among adolescents with versus without disability. METHODS: National Immunization Survey-Child COVID Module data from interviews conducted July 22, 2021-February 26, 2022, were analyzed to assess disability status and type and COVID-19 vaccination status for adolescents (n = 12,445). Prevalence estimates with 95% confidence intervals were calculated; T-tests were conducted. RESULTS: A lower percentage of adolescents with disability received ≥1 dose of COVID-19 vaccine compared to adolescents without disability (52.5% vs. 58.6%), [those with cognition (50.8%) or not performing errands independently (49.5%) disabilities were significantly lower]; and a higher percentage of parents reported intent to definitely vaccinate (9.9% vs. 6.5%) and definitely not vaccinate (14.9% vs. 11.8%) their adolescent. Among the unvaccinated adolescents, parents of those with disability were more likely to report difficulty getting their child vaccinated (19.1% vs. 12.9%), inconvenient vaccination-site operating hours (7.6% vs. 3.9%), difficulty knowing where to get their child vaccinated (7.2% vs. 2.7%), and difficulty getting to vaccination sites (6.0% vs. 3.0%), than parents of those without disability. CONCLUSIONS: Adolescents with disability had lower vaccination coverage compared to adolescents without disability. Parents of adolescents with disability reported higher intent to get their adolescents vaccinated, but among unvaccinated adolescents with disability, parents reported greater difficulty in accessing COVID-19 vaccines. Findings highlight the need for prioritized outreach to increase COVID-19 vaccination for this population.

Crosstalk between TRPV1 and immune regulation in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is the leading indication for corneal transplantation worldwide. Our aim was to investigate the role of transient receptor potential vanilloid subtype 1 (TRPV1) and the associated immune regulation contributing to this pathological condition. Significant upregulation of TRPV1 was detected in the H2O2-induced in vitro FECD model. Based on gene expression microarray dataset GSE142538 and in vitro results, a comprehensive immune landscape was studied and a negative correlation was found between TRPV1 with different immune cells, especially regulatory T cells (Tregs). Functional analyses of the 313 TRPV1-related differentially expressed genes (DEGs) revealed the involvement of TRP-regulated calcium transport, as well as inflammatory and immune pathways. Four TRPV1-related core genes (MAPK14, GNB1, GNAQ, and ARRB2) were screened, validated by microarray dataset GSE112039 and the combined validation dataset E-GEAD-399 & 564, and verified by in vitro experiments. Our study suggested a potential crosstalk between TRPV1 and immune regulation contributing to FECD pathogenesis. The identified pivotal biomarkers and immune-related pathways provide a novel framework for future mechanistic and therapeutic studies of FECD.

A Hybrid Method Fusing Frequency Recognition With Attention Detection to Enhance an Asynchronous Brain-Computer Interface.

OBJECTIVE: One critical problem in controlling an asynchronous brain-computer interface (BCI) system is to discriminate between control and idle states. This paper proposes a hybrid attention detection and frequency recognition method based on weighted Dempster-Shafer theory (ADFR-DS), which integrates information of different aspects of the task from two brain regions, to enhance asynchronous control performance of a steady-state visual evoked potential (SSVEP)-based BCI system. METHODS: The ADFR-DS method utilizes a hybrid architecture to process electroencephalogram (EEG) data from different channels simultaneously: an individualized frequency band based optimized complex network (IFBOCN) algorithm processes neural activity from the prefrontal area for attention detection, and an ensemble task-related component analysis (eTRCA) algorithm processes data from the occipital area for frequency recognition. The ADFR-DS method then fuses their classification results at decision level to generate the final output of the BCI system. A novel weighted Dempster-Shafer fusion method was proposed to enhance the fusion performance. This study evaluated the proposed method using a 40-target dataset recorded from 35 participants. MAIN RESULTS: The proposed method outperformed the eTRCA algorithm in the true positive rate (TPR), true negative rate (TNR), accuracy (ACC) and information transfer rate (ITR). Specifically, ADFR-DS improved the average ACC of eTRCA from 62.71% to 69.30%, and improved the average ITR from 184.28 bits/min to 216.89 bits/min (data length 0.3 s). CONCLUSION: The results suggest that the proposed ADFR-DS method can enhance asynchronous SSVEP-based BCI systems.

Serelaxin Alleviates Fibrosis in Thyroid-Associated Ophthalmopathy via the Notch Pathway.

Fibrosis is the late stage of thyroid-associated ophthalmopathy (TAO), resulting in serious complications. Effective therapeutic drugs are still lacking. We aimed to explore the mechanism of TAO fibrosis and to find a targeted drug. High-throughput RNA sequencing was performed on orbital connective tissues from twelve patients with TAO and six healthy controls. Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database and we identified the hub gene by Cytoscape software. Additionally, the RNA sequencing results were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatic prediction identified the functions of differentially expressed genes (DEGs). Further orbital connective tissue and serum samples of the TAO and control groups were collected for subsequent experiments. Histologic staining, Western blotting (WB), qRT-PCR, enzyme-linked immunosorbent assays (ELISAs), gene overexpression through lentiviral infection or silencing gene by short interfering RNA (siRNA) were performed. We found that the relaxin signaling pathway is an important regulatory pathway in TAO fibrosis pathogenesis. Serelaxin exerts antifibrotic and anti-inflammatory effects in TAO. Furthermore, the downstream Notch pathway was activated by serelaxin and was essential to the antifibrotic effect of serelaxin in TAO. The antifibrotic effect of serelaxin is dependent on RXFP1.

The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with the snRNP biogenesis machinery.

Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. TDRD1, a germ cell-specific gene, is erroneously expressed in more than half of prostate tumors, but its role in prostate cancer development remains elusive. In this study, we identified a PRMT5-TDRD1 signaling axis that regulates the proliferation of prostate cancer cells. PRMT5 is a protein arginine methyltransferase essential for small nuclear ribonucleoprotein (snRNP) biogenesis. Methylation of Sm proteins by PRMT5 is a critical initiation step for assembling snRNPs in the cytoplasm, and the final snRNP assembly takes place in Cajal bodies in the nucleus. By mass spectrum analysis, we found that TDRD1 interacts with multiple subunits of the snRNP biogenesis machinery. In the cytoplasm, TDRD1 interacts with methylated Sm proteins in a PRMT5-dependent manner. In the nucleus, TDRD1 interacts with Coilin, the scaffold protein of Cajal bodies. Ablation of TDRD1 in prostate cancer cells disrupted the integrity of Cajal bodies, affected the snRNP biogenesis, and reduced cell proliferation. Taken together, this study represents the first characterization of TDRD1 functions in prostate cancer development and suggests TDRD1 as a potential therapeutic target for prostate cancer treatment.