Enhancing poststroke hand movement recovery: Efficacy of RehabSwift, a personalized brain-computer interface system.

This study explores the efficacy of our novel and personalized brain-computer interface (BCI) therapy, in enhancing hand movement recovery among stroke survivors. Stroke often results in impaired motor function, posing significant challenges in daily activities and leading to considerable societal and economic burdens. Traditional physical and occupational therapies have shown limitations in facilitating satisfactory recovery for many patients. In response, our study investigates the potential of motor imagery-based BCIs (MI-BCIs) as an alternative intervention. In this study, MI-BCIs translate imagined hand movements into actions using a combination of scalp-recorded electrical brain activity and signal processing algorithms. Our prior research on MI-BCIs, which emphasizes the benefits of proprioceptive feedback over traditional visual feedback and the importance of customizing the delay between brain activation and passive hand movement, led to the development of RehabSwift therapy. In this study, we recruited 12 chronic-stage stroke survivors to assess the effectiveness of our solution. The primary outcome measure was the Fugl-Meyer upper extremity (FMA-UE) assessment, complemented by secondary measures including the action research arm test, reaction time, unilateral neglect, spasticity, grip and pinch strength, goal attainment scale, and FMA-UE sensation. Our findings indicate a remarkable improvement in hand movement and a clinically significant reduction in poststroke arm and hand impairment following 18 sessions of neurofeedback training. The effects persisted for at least 4 weeks posttreatment. These results underscore the potential of MI-BCIs, particularly our solution, as a prospective tool in stroke rehabilitation, offering a personalized and adaptable approach to neurofeedback training.

Post-translational control of NLRP3 inflammasome signaling.

Inflammasomes serve as critical sensors for disruptions to cellular homeostasis, with inflammasome assembly leading to inflammatory caspase activation, gasdermin cleavage, and cytokine release. While the canonical pathways leading to priming, assembly, and pyroptosis are well characterized, recent work has begun to focus on the role of post-translational modifications (PTMs) in regulating inflammasome activity. A diverse array of PTMs, including phosphorylation, ubiquitination, SUMOylation, acetylation, and glycosylation, exert both activating and inhibitory influences on members of the inflammasome cascade through effects on protein-protein interactions, stability, and localization. Dysregulation of inflammasome activation is associated with a number of inflammatory diseases, and evidence is emerging that aberrant modification of inflammasome components contributes to this dysregulation. This review provides insight into PTMs within the NLRP3 inflammasome pathway and their functional consequences on the signaling cascade and highlights outstanding questions that remain regarding the complex web of signals at play.

Robust capital cost optimization of generation and multitimescale storage requirements for a 100% renewable Australian electricity grid.

Transitioning from a fossil-fuel-dependent economy to one based on renewable energy requires significant investment and technological advancement. While wind and solar technologies provide lower cost electricity, enhanced energy storage and transmission infrastructure come at a cost for managing renewable intermittency. Energy storage systems vary in characteristics and costs, and future grids will incorporate multiple technologies, yet the optimal combination of storage technologies and the role of interconnectors in alleviating storage needs are not widely explored. This study focuses on optimal generation-storage capacity requirements to elucidate associated investments. We propose a multitimescale storage solution consisting of three storage categories and an interconnector between Australia's eastern and western grids. Subsequently, through an extensive sensitivity analysis, we investigate the impact of specific storage technologies and cost variations. Our findings demonstrate that the proposed interconnector offers a cost-effective solution, reducing generation and storage power capacity needs by 6 and 14%, respectively, resulting in 4% savings on overall investment costs. Moreover, the study's sensitivity analysis reveals that wind generation provides 50-70% of the energy demand for the least-cost solution. Despite storage inefficiencies, long-duration storage would need to be deployed to support power capacity for 2-4 days, representing 15-40% of peak demand, depending on future technology costs. Subsequently, achieving a fully renewable electricity sector in Australia requires a significant expansion of generation and storage infrastructure, with a 13-fold increase in storage power capacity and a 40-fold increase in storage energy capacity compared to existing levels.

Characterization of flavonoids with potent and subtype-selective actions on estrogen receptors alpha and beta.

The initial step in estrogen-regulated transcription is the binding of a ligand to its cognate receptors, named estrogen receptors (ERα and ERß). Phytochemicals present in foods and environment can compete with endogenous hormones to alter physiological responses. We screened 224 flavonoids in our engineered biosensor ERα and ERß PRL-array cell lines to characterize their activity on several steps of the estrogen signaling pathway. We identified 83 and 96 flavonoids that can activate ERα or ERß, respectively. While most act on both receptors, many appear to be subtype-selective, including potent flavonoids that activate ER at sub-micromolar concentrations. We employed an orthogonal assay using a transgenic zebrafish in vivo model that validated the estrogenic potential of these compounds. To our knowledge, this is the largest study thus far on flavonoids and the ER pathway, facilitating the identification of a new set of potential endocrine disruptors acting on both ERα and ERß.

A novel ERß high throughput microscopy platform for testing endocrine disrupting chemicals.

In this study we present an inducible biosensor model for the Estrogen Receptor Beta (ERß), GFP-ERß:PRL-HeLa, a single-cell-based high throughput (HT) in vitro assay that allows direct visualization and measurement of GFP-tagged ERß binding to ER-specific DNA response elements (EREs), ERß-induced chromatin remodeling, and monitor transcriptional alterations via mRNA fluorescence in situ hybridization for a prolactin (PRL)-dsRED2 reporter gene. The model was used to accurately (Z' = 0.58-0.8) differentiate ERß-selective ligands from ERα ligands when treated with a panel of selective agonists and antagonists. Next, we tested an Environmental Protection Agency (EPA)-provided set of 45 estrogenic reference chemicals with known ERα in vivo activity and identified several that activated ERß as well, with varying sensitivity, including a subset that is completely novel. We then used an orthogonal ERE-containing transgenic zebrafish (ZF) model to cross validate ERß and ERα selective activities at the organism level. Using this environmentally relevant ZF assay, some compounds were confirmed to have ERß activity, validating the GFP-ERß:PRL-HeLa assay as a screening tool for potential ERß active endocrine disruptors (EDCs). These data demonstrate the value of sensitive multiplex mechanistic data gathered by the GFP-ERß:PRL-HeLa assay coupled with an orthogonal zebrafish model to rapidly identify environmentally relevant ERß EDCs and improve upon currently available screening tools for this understudied nuclear receptor.

Investigation of the Common Independent Component Analysis Approaches in Biological Signals for Removing Cardiac Field Artefact from EEG.

Electroencephalography (EEG) signals are often impacted by the cardiac field artefact (CFA), which can compromise EEG analysis. Independent component analysis (ICA) has proven effective in removing such artefacts, including CFA. This paper examines three well-known ICA algorithms commonly utilized in EEG signal processing and assesses their ability to decompose EEG into independent components (ICs) to remove CFA. The paper also investigates whether a new two-level ICA approach can improve performance. Results are evaluated using a synthetic dataset of 10 subjects.

Chemical modulation of gasdermin D activity: Therapeutic implications and consequences.

The gasdermin family of proteins are central effectors of the inflammatory, lytic cell death modality known as pyroptosis. Characterized in 2015, the most well-studied member gasdermin D can be proteolyzed, typically by caspases, to generate an active pore-forming N-terminal domain. At least well-studied three pharmacological inhibitors (necrosulfonamide, disulfiram, dimethyl fumarate) since 2018 have been shown to affect gasdermin D activity either through modulation of processing or interference with pore formation. A multitude of murine in vivo studies have since followed. Here, we discuss the current state of research surrounding these three inhibitors, caveats to their use, and a set of guiding principles that researchers should consider when pursuing further studies of gasdermin D inhibition.

Design of Single-Mode Single-Polarization Large-Mode-Area Multicore Fibers.

In laser science and industry, considerable effort is directed toward designing fibers for fiber laser and fiber amplifier applications, each of which offers a particular advantage over the others. Evanescently coupled multicore fibers, however, have been studied less extensively due to the relatively small mode area in the single-mode regime. Here, by proposing a new structure with stress-applying parts in a 37-core fiber and optimizing this structure through a comprehensive framework, we present 21 solutions characterized by large-mode-area and high beam quality in the single-mode, single-polarization regime. Different fiber designs are optimal for different output parameters. In one design, the mode area can significantly increase to above 880 µm2, which is comparable with that of photonic-crystal fibers. Moreover, besides the single-mode operation, the beam quality factor (M2 factor) of the fundamental mode is considered an output parameter in the bent state and is improved up to 1.05 in another design. A comprehensive tolerance analysis is then performed to assess the performance of the designs under deviations from normal conditions. Moreover, in spite of the shifts in the loss of modes, the proposed high beam quality LMA fibers maintain single-polarization, single-mode operation across a wide range of core pitches, bending orientation angles, and bending radius deviations. Our results highlight the potential of multicore fibers for the efficient operation of fiber lasers and amplifiers.

Structure shows that the BIR2 domain of E3 ligase XIAP binds across the RIPK2 kinase dimer interface.

RIPK2 is an essential adaptor for NOD signalling and its kinase domain is a drug target for NOD-related diseases, such as inflammatory bowel disease. However, recent work indicates that the phosphorylation activity of RIPK2 is dispensable for signalling and that inhibitors of both RIPK2 activity and RIPK2 ubiquitination prevent the essential interaction between RIPK2 and the BIR2 domain of XIAP, the key RIPK2 ubiquitin E3 ligase. Moreover, XIAP BIR2 antagonists also block this interaction. To reveal the molecular mechanisms involved, we combined native mass spectrometry, NMR, and cryo-electron microscopy to determine the structure of the RIPK2 kinase BIR2 domain complex and validated the interface with in cellulo assays. The structure shows that BIR2 binds across the RIPK2 kinase antiparallel dimer and provides an explanation for both inhibitory mechanisms. It also highlights why phosphorylation of the kinase activation loop is dispensable for signalling while revealing the structural role of RIPK2-K209 residue in the RIPK2-XIAP BIR2 interaction. Our results clarify the features of the RIPK2 conformation essential for its role as a scaffold protein for ubiquitination.

Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis.

When activated, gasdermin family members are thought to be pore-forming proteins that cause lytic cell death. Despite this, numerous studies have suggested that the threshold for lytic cell death is dependent on which gasdermin family member is activated. Determination of the propensity of various gasdermin family members to cause pyroptosis has been handicapped by the fact that for many of them, the mechanisms and timing of their activation are uncertain. In this article, we exploit the recently discovered exosite-mediated recognition of gasdermin D (GSDMD) by the inflammatory caspases to develop a system that activates gasdermin family members in an efficient and equivalent manner. We leverage this system to show that upon activation, GSDMD and gasdermin A (GSDMA) exhibit differential subcellular localization, differential plasma membrane permeabilization, and differential lytic cell death. While GSDMD localizes rapidly to both the plasma membrane and organelle membranes, GSDMA preferentially localizes to the mitochondria with delayed and diminished accumulation at the plasma membrane. As a consequence of this differential kinetics of subcellular localization, N-terminal GSDMA results in early mitochondrial dysfunction relative to plasma membrane permeabilization. This study thus challenges the assumption that gasdermin family members effect cell death through identical mechanisms and establishes that their activation in their respective tissues of expression likely results in different immunological outcomes.

Gasdermins and pannexin-1 mediate pathways of chemotherapy-induced cell lysis in hematopoietic malignancies.

Pyroptosis is a mechanism of programmed, necrotic cell death mediated by gasdermins, a family of pore-forming proteins. Caspase-1 activates gasdermin D (GSDMD) under inflammatory conditions, whereas caspase-3 activates GSDME under apoptotic conditions, such as those induced by chemotherapy. These pathways are thought to be separate. However, we found that they are part of an integrated network of gatekeepers that enables pyroptotic cell death. We observed that GSDMD was the primary pyroptotic mediator in cultured blood cells in response to doxorubicin and etoposide, two common chemotherapies for hematopoietic malignancies. Upon treatment, the channel protein pannexin-1 (PANX1), which is stimulated by the initiation of apoptosis, increased membrane permeability to induce K+ efflux-driven activation of the NLRP3 inflammasome and GSDMD. However, either PANX1 or GSDME could also be the primary mediator of chemotherapy-induced pyroptosis when present at higher amounts. The most abundant pore-forming protein in acute myeloid leukemias from patients predicted the cell death pathway in response to chemotherapy. This interconnected network, a multistep switch that converts apoptosis to pyroptosis, could be clinically titratated to modulate cell death with regard to antitumor immunity or tumor lysis syndrome in patients.

Low Cost Digital Implementation of Hybrid FitzHugh Nagumo-Morris Lecar Neuron Model Considering Electromagnetic Flux Coupling.

Digital realization of neuron models, especially implementation on a field programmable gate array (FPGA), is one of the key objectives of neuromorphic research, because the effective hardware realization of the biological neural networks plays a crucial role in implementing the behaviors of the brain for future applications. In this paper, a hybrid FitzHugh Nagumo-Morris Lecar (FNML) neuron model with electromagnetic flux coupling is considered, and two multiplierless piecewise linear (PWL) models, which have similar behaviors to the biological neuron, are presented. A comparison between digital implementation results of the original FNML and PWL models illustrates that, the PWL1 model provides a 65% speed-up with an overall saving (in FPGA resources) of 66.2%, and the PWL2 model yields a 71% speed-up with an overall saving of 78.2%.

Generalization of stochastic-resonance-based threshold networks with Tikhonov regularization.

Injecting artificial noise into a feedforward threshold neural network allows it to become trainable by gradient-based methods and also enlarges the parameter space as well as the range of synaptic weights. This configuration constitutes a stochastic-resonance-based threshold neural network, where the noise level can adaptively converge to a nonzero optimal value for finding a local minimum of the loss criterion. We prove theoretically that the injected noise plays the role of a generalized Tikhonov regularizer for training the designed threshold network. Experiments on regression and classification problems demonstrate that the generalization of the stochastic-resonance-based threshold network is improved by the injection of noise. The feasibility of injecting noise into the threshold neural network opens up the potential for adaptive stochastic resonance in machine learning.

High-performance Mach-Zehnder modulator using tailored plasma dispersion effects in an ITO/graphene-based waveguide.

A high-performance electro-optic Mach-Zehnder modulator (MZM) with outstanding characteristics is proposed. The MZM is in a push-pull configuration that is constructed using an ITO/graphene-based silicon waveguide. A novel idea for engineering of the plasma dispersion effect in an ITO/graphene-based waveguide is proposed so that the modulation characteristics of the MZM are highly improved. Plasma dispersion effects of ITO and graphene layers are tailored in such a way that a large difference between real parts of guided mode effective index of the two arms is achieved while their corresponding imaginary parts are equal. As a result, a very low [Formula: see text] of [Formula: see text] is achieved. To the best of our knowledge, this is one of the lowest [Formula: see text] reported for an electro-optic modulator. In addition, the proposed modulator exhibits a very high extinction ratio of more than 30 dB, low insertion loss of 2.8 dB and energy consumption of as low as 10 fJ/bit, which are all promising for optical communication and processing systems.

Ethnic disparities in publicly-available pulse oximetry databases.

Inaccuracies have been reported in pulse oximetry measurements taken from people who identified as Black. Here, we identify substantial ethnic disparities in the population numbers within 12 pulse oximetry databases, which may affect the testing of new oximetry devices and impact patient outcomes.

TH17 cells promote CNS inflammation by sensing danger signals via Mincle.

The C-type lectin receptor Mincle is known for its important role in innate immune cells in recognizing pathogen and damage associated molecular patterns. Here we report a T cell-intrinsic role for Mincle in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Genomic deletion of Mincle in T cells impairs TH17, but not TH1 cell-mediated EAE, in alignment with significantly higher expression of Mincle in TH17 cells than in TH1 cells. Mechanistically, dying cells release ß-glucosylceramide during inflammation, which serves as natural ligand for Mincle. Ligand engagement induces activation of the ASC-NLRP3 inflammasome, which leads to Caspase8-dependent IL-1ß production and consequentially TH17 cell proliferation via an autocrine regulatory loop. Chemical inhibition of ß-glucosylceramide synthesis greatly reduces inflammatory CD4+ T cells in the central nervous system and inhibits EAE progression in mice. Taken together, this study indicates that sensing of danger signals by Mincle on TH17 cells plays a critical role in promoting CNS inflammation.

GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis.

Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.

Chemical Modulation of Gasdermin-Mediated Pyroptosis and Therapeutic Potential.

Pyroptosis, a lytic form of programmed cell death, both stimulates effective immune responses and causes tissue damage. Gasdermin (GSDM) proteins are a family of pore-forming executors of pyroptosis. While the most-studied member, GSDMD, exerts critical functions in inflammasome biology, emerging evidence demonstrates potential broad relevance for GSDM-mediated pyroptosis across diverse pathologies. In this review, we describe GSDM biology, outline conditions where inflammasomes and GSDM-mediated pyroptosis represent rational therapeutic targets, and delineate strategies to manipulate these central immunologic processes for the treatment of human disease.