299645 research outputs found
Sort by
Development of Nanomolar Affinity Miniprotein Inhibitors Targeting α-Synuclein Aggregation as Promising Therapeutic Agents for Parkinson’s Disease
Full text linkParkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) aggregates in the brain. Developing effective therapies targeting α-syn has been challenging due to its intrinsically disordered nature. In this study, through screening a phage-displayed small ubiquitin-like modifier 1 (SUMO1)(15-55)-biased library, we identified a 41-amino acid miniprotein, PD-6, as a novel nanomolar affinity binder of α-syn. PD-6 had good cell membrane permeability and serum stability. It effectively inhibited α-syn aggregation in SH-SY5Y cells. In Caenorhabditis elegans PD models, PD-6 rescued dopaminergic neuron loss and motor dysfunction to provide protection against neurodegeneration. The binding mode of PD-6 with α-syn was revealed by nuclear magnetic resonance investigation.published_or_final_versio
Non-Inferiority Trials in Stroke Research: What Are They, and How Should We Interpret Them?
No full textRandomized clinical trials are important in both clinical and academic stroke communities with increasing numbers of new design concepts emerging. One of the “less traditional” designs that have gained increasing interest in the last decade is non-inferiority trials. Whilst the concept might appear straightforward, the design and interpretation of non-inferiority trials can be challenging. In this review, we will use exemplars from clinical trials in the stroke field to provide an overview of the advantages and limitations of non-inferiority trials and how they should be interpreted in stroke research
The interplay between epigenomic and transcriptomic variation during ecotype divergence in stickleback
No full textBackground: Populations colonizing contrasting environments are likely to undergo adaptive divergence and evolve ecotypes with locally adapted phenotypes. While diverse molecular mechanisms underlying ecotype divergence have been identified, less is known about their interplay and degree of divergence. Results: Here we integrated epigenomic and transcriptomic data to explore the interactions among gene expression, alternative splicing, DNA methylation, and microRNA expression to gauge the extent to which patterns of divergence at the four molecular levels are aligned in a case of postglacial divergence between marine and freshwater ecotypes of nine-spined sticklebacks (Pungitius pungitius). Despite significant genome-wide associations between epigenomic and transcriptomic variation, we found largely non-parallel patterns of ecotype divergence across epigenomic and transcriptomic levels, with predominantly nonoverlapping (ranging from 43.40 to 87.98%) sets of differentially expressed, spliced and methylated genes, and candidate genes targeted by differentially expressed miRNA between the ecotypes. Furthermore, we found significant variation in the extent of ecotype divergence across different molecular mechanisms, with differential methylation and differential splicing showing the highest and lowest extent of divergence between ecotypes, respectively. Finally, we found a significant enrichment of genes associated with ecotype divergence in differential methylation. Conclusions: Our results suggest a nuanced relationship between epigenomic and transcriptomic processes, with alignment at the genome-wide level masking relatively independent effects of different molecular mechanisms on ecotype divergence at the gene level.</p
Cantonese oral and speech motor assessment for preschool children with and without speech sound disorders
No full textPurposeOral and speech motor abilities are key components of assessments of Cantonese speakers with speech sound disorder (SSD), especially childhood apraxia of speech (CAS). This study aims to investigate the oral and speech motor abilities of Cantonese preschool children with and without SSD using an adapted version of a popular English assessment protocol.MethodsA total of 104 Cantonese-speaking children, aged between 3 to 5 years, were assigned to three main groups: typical development (TD), non-CAS SSD, and CAS. They were tested using the Cantonese Oral and Speech Motor Assessment (COSMA), an adapted version of the Robbins and Klee (RK; 1987) protocol. Sixteen perceptual and acoustic measures were employed to evaluate oral and speech motor abilities in the children, and binary logistic regression models were constructed to assess the predictive values of these measures for broad SSD diagnosis, combining the CAS and non-CAS SSD groups.ResultsStatistically significant differences were observed among the TD, non-CAS SSD, and CAS groups on seven COSMA measures, including measures of oral structures, speech and nonspeech oral functions, and speech motor abilities. Age progression was found on five measures. Total structural score and multisyllabic word accuracy emerged as significant predictors of broad SSD diagnosis.ConclusionThis study supports the preliminary success of the COSMA in differentiating Cantonese preschool children with and without broad SSD. The TD group’s performance offers a reference for local clinical use. Future research should include diverse groups of children with various SSD types to enhance understanding of oral and speech motor skills among Cantonese speakers and related clinical issues.</p
Laryngeal ultrasound-guided adhesive transcutaneous electrodes versus conventional endotracheal electrodes for intraoperative neuromonitoring during thyroid and neck surgery
No full textIntroduction: Conventional intraoperative neuromonitoring during thyroid surgery commonly uses electromyography electrodes embedded in endotracheal tubes. Adhesive transcutaneous electrodes may be a novel, noninvasive and low-cost alternative, but its accuracy and limitations remain less known. This prospective study compared the accuracy of adhesive transcutaneous electrodes placed under laryngeal ultrasound guidance to that of conventional endotracheal tube electrodes and assessed the factors associated with success in adhesive transcutaneous electrodes intraoperative neuromonitoring. Methods: Consecutive patients undergoing open thyroid and neck surgery in a tertiary endocrine surgery unit were prospectively recruited. Before skin incision, the position of vocal cords relative to the thyroid cartilage was marked with laryngeal ultrasonography, and a pair of adhesive transcutaneous electrodes was placed on the overlying skin. Endotracheal tube electrode was used simultaneously. Standardized vagus and recurrent laryngeal nerve stimulation protocol was followed. On each stimulation, electromyography signals were simultaneously recorded by adhesive transcutaneous electrodes and endotracheal tube electrodes and later verified by postoperative flexible laryngoscopy.Results: From 2023 to 2024, 300 nerves at risk from 216 patients were analyzed. Median age was 59 (50—70) years; 72.7% were female. Adhesive transcutaneous electrode electromyography had lower amplitudes for both recurrent laryngeal nerve and vagus nerve (P Conclusion: Laryngeal ultrasound-guided adhesive transcutaneous electrode intraoperative neuromonitoring has comparable sensitivity and negative predictive value to endotracheal tube electrodes and may resolve false endotracheal tube electrodes signal loss. Lower body mass index was associated with improved and comparable accuracy to endotracheal tube electrodes. Adhesive transcutaneous electrodes may be a reliable, low-cost replacement to endotracheal tube electrodes in patients with body mass index <25.</p
Error Analysis of Three-Layer Neural Network Trained With PGD for Deep Ritz Method
No full textMachine learning is a rapidly advancing field with diverse applications across various domains. One prominent area of research is the utilization of deep learning techniques for solving partial differential equations (PDEs). In this work, we specifically focus on employing a three-layer tanh neural network within the framework of the deep Ritz method (DRM) to solve second-order elliptic equations with three different types of boundary conditions. We perform projected gradient descent (PDG) to train the three-layer network and we establish its global convergence. To the best of our knowledge, we are the first to provide a comprehensive error analysis of using overparameterized networks to solve PDE problems, as our analysis simultaneously includes estimates for approximation error, generalization error, and optimization error. We present error bound in terms of the sample size n and our work provides guidance on how to set the network depth, width, step size, and number of iterations for the projected gradient descent algorithm. Importantly, our assumptions in this work are classical and we do not require any additional assumptions on the solution of the equation. This ensures the broad applicability and generality of our results.link_to_subscribed_fulltex
Diversity and Multiplexing for Continuous-Aperture Array (CAPA)-Based Communications
No full textA general fading model for multipath channels between two non-parallel continuous-aperture arrays (CAPAs) is proposed. Building on this model, the performance of diversity and multiplexing achieved by CAPAs over fading channels is analyzed. i) For multiple-input single-output (MISO) and singleinput multiple-output (SIMO) channels, Landau’s eigenvalue theorem is applied to analyze the autocorrelation of the spatial response. Closed-form expressions are derived for the outage probability (OP) and ergodic channel capacity (ECC). Asymptotic analyses in the high signal-to-noise ratio (SNR) regime are conducted to reveal the maximal achievable diversity and multiplexing gains. The diversity-multiplexing trade-off (DMT) is characterized, along with the array gain within the DMT framework. ii) For multiple-input multiple-output (MIMO) channels, a wavenumber-domain-based transmission framework is proposed to leverage the spatial degrees of freedom offered by CAPAs. Asymptotic approximations for the OP and ECC are derived, and the DMT is explored. The performance of CAPAs is further compared with that of conventional spatially-discrete arrays (SPDAs). Analytical and numerical results demonstrate that: i) CAPAs achieve a lower OP and higher ECC than SPDAs; ii) CAPAs achieve the same DMT as SPDAs with antenna spacing no larger than half a wavelength while attaining a higher array gain; and iii) CAPAs outperform SPDAs with antenna spacing greater than half a wavelength in terms of DMT.link_to_subscribed_fulltex
Near-Field Motion Parameter Estimation: A Variational Bayesian Approach
No full textA near-field motion parameter estimation method is proposed. In contrast to far-field sensing systems, the near-field sensing system leverages spherical-wave characteristics to enable full-vector location and velocity estimation. Despite promising advantages, the near-field sensing system faces a significant challenge, where location and velocity parameters are intricately coupled within the signal. To address this challenge, a novel subarray-based variational message passing (VMP) method is proposed for near-field joint location and velocity estimation. First, a factor graph representation is introduced, employing subarray-level directional and Doppler parameters as intermediate variables to decouple the complex location-velocity dependencies. Based on this, the variational Bayesian inference is employed to obtain closed-form posterior distributions of subarray-level parameters. Subsequently, the message passing technique is employed, enabling tractable computation of location and velocity marginal distributions. Two implementation strategies are proposed: 1) System-level fusion that aggregates all subarray posteriors for centralized estimation, or 2) Subarray-level fusion where locally processed estimates from subarrays are fused through Guassian product rule. Cramér-Rao bounds for location and velocity estimation are derived, providing theoretical performance limits. Numerical results demonstrate that the proposed VMP method outperforms existing approaches while achieving a magnitude lower complexity. Specifically, the proposed VMP method achieves centimeter-level location accuracy and sub-m/s velocity accuracy. It also demonstrates robust performance for high-mobility targets, making the proposed VMP method suitable for real-time near-field sensing and communication applications.link_to_subscribed_fulltex
Distributed Multi-Antenna GPS Spoofing Attack using Off-The-Shelf Devices
No full textGlobal Positioning System (GPS) signals, though critical to numerous civilian and industrial applications, remain susceptible to spoofing due to their unencrypted nature. While many existing defenses focus on single-Antenna spoofing, multi-Antenna spoofing has been theorized as a significantly more potent threat. However, practical realizations of multi-Antenna spoofing have been limited by the stringent requirement of nanosecond-level synchronization. In this paper, we present the first low-cost, end-To-end implementation of a distributed multi-Antenna GPS spoofing attack using off-The-shelf devices. We systematically examine the technical prerequisites, establishing sub-50 ns alignment among spoofing signals as the requirement for successfully spoofing standard GPS receivers. Building on this analysis, we design a multi-Antenna spoofing system that continuously monitors and adaptively adjusts relative signal timing, mitigating hardware imperfections and oscillator drift in real time. Our prototype, built using HackRFs and Raspberry Pis, demonstrates that it can successfully spoof devices such as Android phones and commercial GPS receivers. Through controlled experiments in an anechoic chamber, we show that our attack can steer these receivers to falsified locations with an average error of 30∼m, while also evading detection by robust angle-of-Arrival-based systems. Finally, we discuss practical considerations for wide-Area deployments, along with countermeasures that may mitigate this emerging threat.link_to_subscribed_fulltex