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Given the growing role of non-pharmacological rehabilitation in Parkinson's disease and the limited comparative evidence between different exercise modalities, this study aimed to compare the effectiveness of Tai Chi and combined resistance-stretching exercise on motor symptoms, physical function, and quality of life (QOL) in patients with Parkinson's disease (PD). A three-armed randomized controlled trial was conducted in patients with PD at Hoehn and Yahr (H&Y) stages 2-3. The motor symptoms of patients with PD were assessed using the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), Freezing of Gait Questionnaire (FOGQ), Timed Up and Go, Parkinson's Disease Questionnaire-39 (PDQ-39), while muscle fitness was evaluated using the functional reach, 30s arm curl, 30s chair stand, and grip strength tests before and after a 14-week intervention. Both exercise groups showed statistically significant and potentially clinically meaningful improvements in total UPDRS-III scores, with varying degrees of change observed across different dimension scores. Tai Chi was particularly effective in enhancing muscular endurance, motor control, and balance, contributing to improved overall QOL. The combined resistance-stretching group showed more significant improvements in muscular strength, functional fitness, also resulting in improved QOL. No significant differences in FOGQ score were observed between the two exercise groups. Both Tai Chi and combined resistance-stretching exercises are effective non-pharmacological interventions for improving core motor symptoms, physical function and QOL in patients with early to mid-stage Parkinson's disease, with Tai Chi particularly benefiting muscular endurance, motor control and balance ability.

In this essay, I consider the "social life" of digital twins in translational medicine, exploring how the United States is culturally unprepared for the arrival of digital twins at whole person scales. By looking more closely at our anticipated individual and collective interactions with digital twins for biomedical research and health care purposes, I attempt to highlight how our current approach to biomedical innovation could impede the realization of precision medicine rather than enable it. Extensive translational bioethics research-including specifically more deliberate anthroengineering research-is urgently needed so that we can better understand how these dynamic, data intensive, artificial intelligence-enabled technologies can be responsibly developed, organized, and engaged, and so that we can co-create the necessary cultural conditions for us all to thrive.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) and constitutes approximately 15-20% of all BC cases. This subtype has the most aggressive behavior and the worst prognosis. Numerous studies have been conducted over the past several decades to address the lack of clinically available treatment options. In particular, potential markers targeting effective treatment options have been actively studied. However, these efforts were hindered by the complex mechanisms of TNBC, and no study has demonstrated a model with a predictive performance exceeding 0.85. This study developed TNBC prognosis predictive models with a predictive performance exceeding 0.94. Applying the nine selected markers to five independent datasets demonstrated their potential as TNBC-specific prognostic markers. Most of these genes (including GPR61, PZP, IGFL1, and AHCTF1) are associated with overall survival (OS) in patients with TNBC. Based on these results, these nine selected genes may serve as prognostic markers for OS in patients with TNBC.

Genistein (GEN), a soy-derived isoflavonoid and phytoestrogen, exhibits diverse biological activities against allergic and hypersensitivity reactions, autoimmune disorders, infectious diseases, and cancer. Its immunomodulatory properties are crucial to these effects however, clinical translation remains limited due to the complexity and pronounced context dependence of its immune actions. This review critically summarizes experimental evidence on GEN-mediated immunomodulation across innate and adaptive immune compartments, including its effects on cytokine regulation and key molecular signaling pathways. GEN has been shown to modulate dendritic cells, mast cells, macrophages, T cells, B cells, and natural killer cells through both estrogen receptor-dependent and -independent mechanisms, involving pathways such as ERK, NF-κB, p53, and IL-18 receptor signaling. Notably, these immunomodulatory effects are influenced by multiple variables, including cell type, dose, sex, hormonal milieu, and developmental stage, presenting significant challenges for clinical translation. While GEN demonstrates substantial immunomodulatory potential, its highly context-specific actions necessitate disease-relevant preclinical validation and carefully tailored therapeutic strategies that account for dosage, target immune cells, hormonal status, and patient sex. Addressing these factors, together with advances in formulation approaches to improve bioavailability, will be essential for the rational development of GEN as a precision immunomodulatory agent.

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To identify structural alterations of Descemet's membrane (DM) in bullous keratopathy (BK) and to explore their association with intracellular dark endothelial spots (IDESs) observed by specular microscopy. This multicenter, retrospective, observational study included 75 eyes that underwent endothelial keratoplasty for corneal endothelial dysfunction. Based on preoperative clinical diagnosis, eyes were classified as having Fuchs endothelial corneal dystrophy (FECD)-related or non-FECD BK. DM specimens were collected during endothelial keratoplasty and analyzed as flat-mounted preparations using phase-contrast microscopy. IDESs were evaluated preoperatively by masked assessment using specular microscopy. Among the 75 eyes, 25 were clinically diagnosed with FECD. Of the remaining 50 eyes with BK, 15 showed no characteristic histological abnormalities, 11 exhibited guttae-like changes, and 24 demonstrated a distinct and previously unrecognized DM alteration, termed dome-shaped protrusions (DSPs). Specular microscopy images suitable for IDES evaluation were available in a subset of cases. IDESs were detected in 10 of 18 DSP-positive eyes and in 1 of 10 DSP-negative eyes, indicating a significant association between DSPs and IDESs (odds ratio 11.25; P < 0.05). DSPs represent a distinct structural alteration of the DM in non-FECD BK and are significantly associated with IDESs observed by specular microscopy. These findings provide insight into the heterogeneity of endothelial failure in BK and suggest a link between clinical imaging findings and underlying DM morphology. Dome-shaped protrusions provide a histopathological correlate for intracellular dark endothelial spots observed by specular microscopy and may support improved phenotyping of endothelial dysfunction in non-Fuchs endothelial corneal dystrophy bullous keratopathy.

In extracorporeal therapies such as cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO), the transport of blood through artificial circulation frequently results in the rupture of erythrocytes, releasing hemoglobin (Hb) into the plasma (fHb), and exhausting the body's supply of the natural fHb scavenger-haptoglobin (Hp). This complication, known as mechanical hemolysis, results in the release of fHb and its downstream heme-containing degradation products and is associated with multi-organ dysfunction and adverse outcomes. Current strategies for mitigating hemolysis in extracorporeal circuits are either resource-intensive or nonspecific. Here, we describe the fabrication and benchtop evaluation of an fHb-adsorbing device intended as an adjunctive, intermittent, time-limited approach to reduce fHb. Human Hp was immobilized onto a cross-linked agarose resin and loaded into a packed-bed device compatible with whole-blood perfusion. Under controlled recirculation conditions, the device demonstrated the ability to capture fHb and attenuate its accumulation relative to control. A regenerative protocol was developed to disrupt the Hp-Hb complexes and restore a substantial fraction of Hp binding activity. These findings support both the feasibility of immobilized Hp for selective fHb capture under benchtop conditions as well as the need for further device optimization and evaluation in more physiologically representative extracorporeal models. https://links.lww.com/ASAIO/B922.

The widespread use of social media has facilitated the recognition of personality from user-generated online content. While numerous applications exist across diverse domains, such as recommender systems, most current studies focus on superficial, statistical, and explicit user content, thereby neglecting latent knowledge. In this study, we propose a method for uncovering latent psycholinguistic understanding at deeper levels of user data to enhance personality prediction through natural language processing. The proposed approach leverages fine-tuning of a domain-specific Bidirectional Encoder Representations from Transformers (BERT) model for sentence-level feature extraction and enriches the output by incorporating emotional information. This process emphasizes salient words through a single-way attention mechanism. Our single-way attention mechanism propagates information from highlighted words to the overall extracted knowledge. Subsequently, using the embeddings from the previous stage as node features, we construct a graph. A dynamic, task-oriented learning approach is then employed to determine the graph edges, using a neural network to connect different pairs of nodes. Finally, a graph neural network is combined with a classifier to predict personality traits. Experimental results demonstrate the effectiveness of the proposed model, achieving 80.27% accuracy on the Essays dataset and outperforming existing approaches. Furthermore, several ablation studies were conducted to investigate the impact of various components and parameters of the proposed architecture.

Collagen, a central component of the extracellular matrix (ECM), precisely regulates tissue mechanical properties and biological functions through hierarchical assembly, playing a vital role in maintaining homeostasis. However, the molecular mechanism of assembly remains poorly understood, limiting insights into tissue remodeling, aging, and ECM-related diseases. Here, we employ time-resolved cryo-electron microscopy to resolve two critical hierarchical intermediates in fibrillar collagen assembly, proposing the 3D collagen assembly pathway. We identify a metastable triple-helical conformation as the fundamental assembly unit, whose structural lability propagates through the assembly cascade, rendering the process sensitive to microenvironmental perturbations. Through hierarchical assembly, metastable intermediates achieve enhanced structural stability, culminating in the formation of stable collagen that retains its integrity under physiological conditions. In contrast, structural defects in intermediates lead to aberrant assembly and disruption of ECM integrity. Functional assays reveal that intermediates lacking D-band retain biological activity. Our findings redefine the fibrillar collagen assembly as a hierarchical, time-resolved cascade driven by metastable intermediates and propose the fundamental F-Z-F rules. The metastable triple helix provides a structural basis for hierarchical assembly and suggests a potential link between abnormal fibrillar collagen assembly and aging-related matrix dysfunction, offering valuable insights into collagen assembly and its role in aging diseases.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness, primarily associated with retinal pigment epithelial (RPE) cell degeneration. Although RPE cell therapy has emerged as a promising strategy for AMD, maintaining RPE cell attachment, organization, and functional characteristics remains a major challenge. In this study, free-standing chondroitin sulfate (CS)/collagen (Col) multilayered films were fabricated via spin-coating-assisted layer-by-layer (LbL) assembly and evaluated in vitro as preliminary Bruch's membrane (BM)-mimetic platform for supporting RPE growth and preserving cellular functionality. Genipin cross-linking improved the mechanical stability of the films and reduced their swelling behavior. ARPE-19 cells cultured on the 2&#x202f;h cross-linked films showed improved attachment and proliferation compared with uncross-linked films, together with detectable RPE65 expression and several RPE-related functional features, including apical-basal differences in pigment epithelium-derived factor (PEDF) secretion, phagocytosis of labeled photoreceptor outer segments (POS), and formation of microvilli-like structures. Collectively, these findings suggest that CS/Col free-standing films can support ARPE-19 cell growth and maintain several RPE-related phenotypic and functional features in vitro, providing a preliminary BM-mimetic platform for future RPE culture studies.

Nanoscale bilayer mimetics such as protein or polymer-based nanodiscs are versatile tools to study the physical chemistry of lipid bilayers or the structures and functions of membrane proteins. Here, we introduce DNA-lipid nanodiscs (DLNs) in which the interface between hydrophobic lipids and the charged DNA is mediated through amphiphilic poly(ethylene)glycol (PEG). For this, we modified oligonucleotides with PEG and hybridized them to a single-stranded ring to form functionalized minicircles with a well-defined diameter. The center of these minicircles can be filled with a lipid bilayer through addition of detergent-solubilized lipids followed by detergent removal. Simulations reveal that the methylene groups in PEG form dynamic interactions with the acyl chains of lipids, effectively shielding the hydrophobic mismatch. As proof of concept toward incorporation of complex membrane proteins, we inserted the biotinylated transmembrane domain of synaptobrevin into these nanodiscs and bound them to streptavidin-modified quantum dots as a marker for successful incorporation. We envision these atomically precise, modular DNA scaffolds to be widely applicable in future studies of membrane proteins and nanoscale lipid membranes.

Spasticity is a frequent neuromuscular impairment associated with cerebral palsy, stroke, and spinal cord injury, commonly assessed using subjective clinical scales. This exploratory pilot study aimed to develop and preliminarily validate a multimodal instrument for the objective quantification and stratification of spasticity in nine individuals (3 female, 6 male) with upper-limb spasticity due to cerebral palsy (n&#x2009;=&#x2009;5) or stroke (n&#x2009;=&#x2009;4). A wearable system integrating surface electromyography, inertial measurement units, and force sensing resistors was designed to simultaneously capture muscle activation, joint kinematics, and generalized resistance force during standardized passive mobilizations. Simple indicators six area under the curve-based indicators were derived: force, sEMG, and angular velocity under two conditions (R1, R2) and given distinct weights depending on their contribution. Principal component analysis revealed that three latent components accounted for 83.86% of the total variance observed across participants. Based on these indicators, a Composite Index was constructed using min-max normalization and weighted linear aggregation. Within the pilot study, the Composite Index could differentiate between spasticity severity levels (F&#x2009;=&#x2009;6.38, p&#x2009;=&#x2009;0.0327, &#x3b7;&#xb2;&#x2009;=&#x2009;0.68), with sEMG activity during slow stretch (AUC sEMG R2) the most influential contributor indicators. The proposed multimodal instrument demonstrates preliminary feasibility as a non-invasive and portable approach for objective spasticity quantification, warranting further validation in larger cohorts.

Colicin E3 (E3-rRNAse) abolishes protein biosynthesis in bacteria by cleaving 16S rRNA in the decoding centre. The RtcB2-PrfH 16S rRNA repair module prevents cellular death upon exposure to E3-rRNAse in E. coli. Upon overexpression, RtcB2 RNA ligase alone was capable of relieving E. coli growth, which was inhibited by E3-rRNAse. Using in vitro ribosome repair system based on recombinant components, we demonstrated that RtcB2 alone could repair E3-rRNAse cleaved 30S subunits and 70S ribosomes. The peptide chain release factor homolog (PrfH), which is able to hydrolyse peptidyl-tRNA bound by colicin-cleaved ribosomes, boosts RtcB2 ligation efficiency for damaged ribosomes engaged in translation.

The translation of big data analytics and artificial intelligence (AI) into clinical decision support systems (CDSSs) has advanced from proof of concept to real-world clinical practice. AI-informed CDSSs show measurable improvements in diagnostic accuracy, risk stratification, resource use, and patient outcomes compared to traditional models, offering the potential to assist clinicians in managing symptom complexity and uncertainty in health care delivery. Despite this potential, access to large amounts of high-quality and granular data remains one of the most significant bottlenecks to AI-enabled CDSSs. We argue that as health care systems increasingly adopt data-driven decision support, addressing the challenges of data accessibility and protection is essential to realizing the full potential of AI in clinical medicine. We use selected case examples of AI-informed CDSSs in oncology, organ transplantation, diabetic retinopathy, epilepsy, spinal cord injury, rare disease diagnosis, and emergency medicine to illustrate opportunities and challenges related to AI's potential to improve patient outcomes. We discuss public and semipublic, medical institutional and commercial, and government and national data sources that are currently available for the development of CDSSs and highlight the practical and ethical constraints associated with these data. We consider alternative data resources and ways in which health care systems can strengthen data ecosystems to increase AI-driven CDSS efficacy and implementation to improve patient outcomes.

Early-stage diagnosis of paroxysmal atrial fibrillation (PAF) is challenging owing to its asymptomatic nature. However, the genetic factors underlying PAF and predictive utility of polygenic risk scores (PRSs) for PAF in Asian populations remain elusive. We aimed to explore the PAF-associated genetic variants in a Japanese cohort and evaluate the predictive performance of PAF-specific PRSs. This study included 2,604 participants. Following exclusion, quality control, and genotype imputation, a genome-wide association study (GWAS) was conducted. The predictive performance of 30 sets of PRS models constructed across various thresholds was evaluated using three machine learning methods. Model performance was assessed using area under the curve (AUC) and SHapley Additive exPlanations (SHAP). The GWAS using 1,038 PAF cases and 744 controls identified 82 genome-wide significant variants (P&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10-8), all on chromosome 4q25. Of these, 80 variants clustered upstream of PITX2, and two were located in LINC01438. Fine mapping identified two independent intergenic signals, with rs2200732 as the lead single-nucleotide polymorphism. The best PRS-only model achieved an AUC of >0.70, which was improved up to 0.737 in additive models incorporating both PRS and clinical variables. SHAP analysis consistently ranked PRS as the most influential predictor among the clinical variables included in this study. These results suggest that genetic risk, particularly at the established 4q25/PITX2 locus, contributes substantially to PAF susceptibility in this Japanese cohort and that PRS may improve early risk stratification when integrated with clinical risk factors.

Focused ultrasound (FUS) and microbubbles can transiently increase blood brain barrier (BBB) permeability, yet BBB opening (BBBO) verification relies mainly on contrast-enhanced MRI, offering limited insight into the molecular consequences of barrier modulation. Sonobiopsy, which uses FUS induced BBBO to release brain derived molecules into the bloodstream, provides a molecular readout from blood samples. Nanobubbles (NBs) are smaller agents that circulate more effectively in the brain microvasculature and have shown enhanced BBBO in capillaries. Here, we establish NB-based sonobiopsy as a platform for enhanced biomarker efflux and molecular sensitivity, and apply it to define the proteomic signature of BBBO in healthy and glioblastoma (GBM) models. Plasma collected before and after NB-mediated FUS underwent data-independent acquisition-based mass spectrometry, revealing post-BBBO changes in healthy and tumor bearing mice. In healthy cohorts, 77 proteins were reproducibly altered after BBBO. Six proteins (Dpysl3, Myl1, Mybpc1, Vsig4, Krt33a, Krtap6-5) were detectable only after BBBO in healthy mice. In 005 glioma bearing mice, the BBBO signature identified in healthy animals was preserved with clear pre- vs post-BBBO separation. Candidate BBBO-associated proteins identified in the NB cohort were subsequently evaluated in an MB cohort, where the pre-to-post BBBO changes observed with NBs were not reproduced. These findings establish NB-mediated proteomic sonobiopsy as a promising method for BBBO verification across healthy and disease-relevant conditions and support the development of scalable molecular readouts for BBBO confirmation. This platform may also complement disease-focused sonobiopsy approaches, including protein-based biomarker studies in neuro-oncology.

Rheumatic diseases are chronic, immune-mediated conditions characterized by significant heterogeneity in presentation and disease course. However, current clinical approaches often rely on snapshot-based assessments that fail to capture the complex longitudinal evolution of these conditions. To address these limitations and support the implementation of precision medicine, we present the design for the Rheumatic Digital Twin, a novel, modular conceptual framework intended to integrate heterogeneous multimodal data, ranging from electronic health records and clinical notes to imaging and omics, into a dynamic, computational representation of the patient journey. Our theoretical architecture addresses challenges related to data silos and variable availability of data modalities through a multistage approach that envisions the use of domain-specific foundation models to independently process distinct data modalities. To effectively model the temporal progression inherent in chronic diseases, the proposed design utilizes Transformer architectures, leveraging self-attention mechanisms to treat patient events, such as lab results or medication changes, as sequential data tokens. We describe how these unimodal representations would subsequently be fused via joint embedding techniques to construct a shared, multimodal representational space. Envisioned to function analogously to a recommender system, the Rheumatic Digital Twin framework is modeled to map patients into a latent space where proximity reflects clinical and biological similarity. By identifying "nearest neighbors," historical patients with comparable trajectories, the system aims to enable in silico cohorting, theoretically allowing clinicians to forecast key clinical events, predict treatment responses, and identify likely disease courses based on the outcomes of similar peers.

Previous studies have shown that additional cognitive load from a secondary task can adversely affect movement performance. However, how externally provided auditory pacing influences motor and neural responses under dual-task conditions remains unclear. This study employed a repeated-measures experimental design, studying eighteen young adults (Mean age 23.5&#x2009;&#xb1;&#x2009;4 years) who underwent three conditions: (1) foot tapping only (single task), (2) foot tapping and a mental task (dual task), and (3) foot tapping, mental task, and auditory pacing biofeedback (dual task&#x2009;+&#x2009;biofeedback). Ankle joint movements using Xsens IMU's (Inertial Motion Units) and brain activities using EEG (electroencephalography) were measured in these three conditions. Results showed that dual tasks significantly reduced (p&#x2009;<&#x2009;0.01) the range of motion and increased (p&#x2009;<&#x2009;0.05) the variability of ankle joint range of motion, suggesting a decline in foot tapping performance compared to the single-task condition. The decline was accompanied by significant increases (p&#x2009;<&#x2009;0.05) in relative high-beta power in EEG, consistent with heightened cognitive-motor demand during dual-tasking. In the dual-task&#x2009;+&#x2009;biofeedback condition, kinematic measures returned to values statistically indistinguishable from the single-task condition and response times in the cognitive task were significantly reduced, without a loss of accuracy. The relative high-beta power was also significantly reduced, compared with the dual-task condition, which may reflect increased entrainment to external cues or a reduction in cognitive load. These results support the role of auditory pacing in facilitating movement performance under dual-tasking conditions, while highlighting the need for future studies to dissociate entrainment effects from changes in cognitive workload.

Crystal Violet (CV) and Reactive Black 5 (RB5), representative of the triphenylmethane and azo dye classes, are extensively used in the textile industry and are recognized as major contributors to aquatic pollution. Their structural stability and resistance to biodegradation lead to environmental persistence and potential toxicity. In this paper, a non-equilibrium cold plasma-based pin-to-plate dielectric barrier discharge (P2PDBD) source was employed for the degradation of dye solutions. The effects of plasma discharge power, dye concentration, and the chemical composition of the water matrix were systematically studied. With increasing salt concentration from 0 to 25&#xa0;mg L-1, Sodium carbonate synergistically enhanced CV degradation to near completion within minutes but inhibited RB5 by 38%, while sodium chloride, sulfate, and nitrate reduced CV degradation by 16%, 11%, and 8.26%, and RB5 degradation by 39%, 8.36%, and 7.7%, respectively. Radical scavenging experiments using methanol and isopropyl alcohol confirmed that hydroxyl radicals played a dominant role in the degradation process. The initial pH also affected degradation, with CV degrading more rapidly under basic conditions, while RB5 showed reduced efficiencies under both acidic and basic environments. Structural changes and degradation pathways were further elucidated through high-resolution mass spectroscopy, UV-Vis spectroscopy, and surface-enhanced Raman spectroscopy. Post-treatment phytotoxicity and cytotoxicity evaluations indicated that the treated water was non-toxic and, under controlled conditions, may also support early plant growth due to the presence of nitrates, suggesting that plasma-treated effluents are safe and suitable for reuse in agricultural and environmental applications.