Search Results (5,360)

Leaf senescence is a developmental process that allows nutrients to be remobilized and transported to sink organs. Previously, papain-like cysteine proteases (PLCPs) have been found to be highly expressed during leaf senescence in different plant species. In this study, we analyzed active PLCPs in barley (Hordeum vulgare L.) leaves during the terminal stage of natural senescence. Anion exchange chromatography of protein extracts from barley leaves, harvested six weeks after anthesis, followed by activity assays using the substrates Z-FR-AMC and Z-RR-AMC, revealed a single prominent peak corresponding to active PLCPs. This hydrolytic activity was completely inhibited by E-64, a potent and irreversible inhibitor of cysteine proteases. Fractions enriched for PLCP activity were affinity-labeled with DCG-04 and subjected to SDS-PAGE fractionation, separating two major bands at 43 and 38 kDa. These bands were analyzed using tandem mass spectrometry, allowing the identification of eleven PLCPs. Identified enzymes belong to eight PLCP subfamilies, including CTB/cathepsin B-like (HvPap-19 and -20), RD19/cathepsin F-like (HvPap-1), ALP/cathepsin H-like (HvPap-12 or aleurain), SAG12/cathepsin L-like A (HvPap-17), CEP/cathepsin L-like B (HvPap-14), RD21/cathepsin L-like D (HvPap-6 and -7), cathepsin L-like E (HvPap-13 and -16), and XBCP3 (HvPap-8). Among the identified PLCPs, HvPap-6 was the most abundant. Peptides corresponding to HvPap-6 were identified in both the 43 kDa and 38 kDa bands in approximately the same quantity based on total spectral count. Thus, our results indicate that two active HvPap-6 isoforms can be isolated from barley leaves at late senescence. Full article

Selenoprotein thioredoxin reductase 1 (TXNRD1) is frequently upregulated in various cancer cells to sustain cellular redox homeostasis, and its inhibition has emerged as a promising anti-cancer strategy. In this study, we identified PK11007, a thiol-modifying compound previously characterized as a p53 reactivator, as a potent inhibitor of TXNRD1. PK11007 irreversibly inhibited recombinant TXNRD1 in a time- and dose-dependent manner. Using differential scanning fluorimetry (DSF) and LC–MS/MS analysis, we confirmed that PK11007 covalently modifies the C-terminal redox motif (Cys⁴⁹⁷-Sec⁴⁹⁸) of TXNRD1. In non-small cell lung cancer (NSCLC) H1299 cells, PK11007-induced TXNRD1 inhibition disrupted cellular redox balance, leading to impaired autophagy flux and cell death. Similar autophagy suppression was observed in TXNRD1-knockdown cells, as well as pharmacological inhibition of TXNRD1 by Auranofin (AF) and TXNRD1 inhibitor 1 (TRi-1). Taken together, these findings highlight that oxidative stress contributes to the cytotoxic effects of PK11007 and uncover autophagy disorder as a downstream consequence of TXNRD1 inhibition. Full article

Glaucoma is a leading cause of irreversible blindness, and animal models are essential for studying its pathophysiology and testing therapeutic strategies. In this study, a novel hydrogel-based approach was developed and evaluated to induce experimental glaucoma in mice, using composites of hyaluronic acid (HA) and the self-assembling peptide fluorenylmethoxycarbonyl-diphenylalanine (FmocFF). Two formulations with different HA-to-FmocFF ratios were injected either intracamerally or intravitreally in C57BL/6 mice. Intraocular pressure (IOP) was monitored over 21 days, and retinal tissues were analyzed histologically and immunohistochemically. Significant IOP elevation was observed in one hydrogel formulation (Mixture B), yet without detectable retinal ganglion cell loss. A significant reduction in retinal ganglion cell (RGC) density, independent of IOP changes or injection site, was observed in Mixture A. Histological staining confirmed successful delivery and localization of the hydrogel in the anterior chamber, and no evidence of gliosis, microglial activation, or increased apoptosis was revealed by immunostaining. Collectively, these data position the HA-FmocFF hydrogel as a proof-of-concept that advances glaucoma model development, although it does not yet recapitulate the full disease. This model may facilitate future studies of neuroprotection and disease-modifying therapies in glaucoma without confounding inflammatory responses. Full article

Plastic pollution has emerged as a pervasive and systemic driver of ecological and biogeochemical disruption in freshwater and marine environments. Unlike natural materials that circulate within closed biogeochemical loops, synthetic polymers predominantly follow unidirectional and irreversible trajectories, a phenomenon we describe as “irreversible plastic transport.” These flows culminate in sedimentary entrapment, where plastics persist as long-term ecological stressors and potential vectors of contaminant transfer. Recent global syntheses indicate that sedimentary microplastic loads can exceed 27,000 particles/kg dry weight in certain river systems, highlighting the urgency of sediment-inclusive risk assessments. This review synthesizes interdisciplinary findings to conceptualize plastics as both pollutants and governance challenges. We highlighted the dominant transport pathways of micro- and nanoplastics and emphasize that sedimentary sinks are critical long-term retention zones. Current monitoring frameworks often underestimate sedimentary burdens by focusing on surface water and overlooking subsurface ecological legacies. We propose an integrated governance approach combining cross-media monitoring, Earth system modeling, and adaptive policies to address these persistent synthetic agents. Embedding plastic dynamics within comprehensive risk assessment frameworks is essential for sustainable water management during the Anthropocene. Our synthesis supports risk-based decision-making and encourages proactive, transdisciplinary global governance strategies that integrate sediment-focused monitoring and long-term ecological risk management. Full article

Reliable power generation from solar cells is critical for spacecraft operation. High-energy laser irradiation poses a significant threat, as it can potentially cause irreversible damage to solar cells, which is difficult to detect remotely using conventional techniques such as radar or optical imaging. Spectral detection offers a potential approach through unique “spectral fingerprints,” but the spectral characteristics of laser-damaged solar cells remain insufficiently documented. This study investigates the scattering spectral characteristics of triple-junction GaAs (Gallium Arsenide) solar cells subjected to nanosecond pulsed laser irradiation to establish spectral signatures for damage assessment. GaAs solar cells were irradiated at varying energy densities. Bidirectional Reflectance Distribution Function (BRDF) spectra (400–1200 nm) were measured. A thin-film interference model was used to simulate damage effects by varying layer thicknesses, thereby interpreting experimental results. The results demonstrate that as the laser energy density increases from 0.12 to 2.96 J/cm², the number of absorption peaks in the visible range (400–750 nm) decreases from three to zero, and the oscillation in the near-infrared range vanishes completely, indicating progressive damage to the GaInP (Gallium Indium Phosphide) and GaAs layers. This study provides a spectral-based approach for remote assessment of laser-induced damage to solar cells, which is crucial for satellite health monitoring. Full article

Background: Papilledema, an ophthalmic finding associated with increased intracranial pressure, is often induced by dermatological medications, including corticosteroids, isotretinoin, and tetracyclines. Early detection is crucial for preventing irreversible optic nerve damage, but access to ophthalmologic expertise is often limited in rural settings. Artificial intelligence (AI) may enable the automated and accurate detection of papilledema from fundus images, thereby supporting timely diagnosis and management. Objective: The primary objective of this study was to explore the diagnostic capability of ChatGPT-4o, a general large language model with multimodal input, in identifying papilledema from fundus photographs. For context, its performance was compared with a ResNet-based convolutional neural network (CNN) specifically fine-tuned for ophthalmic imaging, as well as with the assessments of two human ophthalmologists. The focus was on applications relevant to dermatological care in resource-limited environments. Methods: A dataset of 1094 fundus images (295 papilledema, 799 normal) was preprocessed and partitioned into a training set and a test set. The ResNet model was fine-tuned using discriminative learning rates and a one-cycle learning rate policy. GPT-4o and two human evaluators (a senior ophthalmologist and an ophthalmology resident) independently assessed the test images. Diagnostic metrics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and Cohen’s Kappa, were calculated for each evaluator. Results: GPT-4o, when applied to papilledema detection, achieved an overall accuracy of 85.9% with substantial agreement beyond chance (Cohen’s Kappa = 0.72), but lower specificity (78.9%) and positive predictive value (73.7%) compared to benchmark models. For context, the ResNet model, fine-tuned for ophthalmic imaging, reached near-perfect accuracy (99.5%, Kappa = 0.99), while two human ophthalmologists achieved accuracies of 96.0% (Kappa ≈ 0.92). Conclusions: This study explored the capability of GPT-4o, a large language model with multimodal input, for detecting papilledema from fundus photographs. GPT-4o achieved moderate diagnostic accuracy and substantial agreement with the ground truth, but it underperformed compared to both a domain-specific ResNet model and human ophthalmologists. These findings underscore the distinction between generalist large language models and specialized diagnostic AI: while GPT-4o is not optimized for ophthalmic imaging, its accessibility, adaptability, and rapid evolution highlight its potential as a future adjunct in clinical screening, particularly in underserved settings. These findings also underscore the need for validation on external datasets and real-world clinical environments before such tools can be broadly implemented. Full article

Aqueous zinc-ion batteries (ZIBs) have emerged as a promising candidate for large-scale energy storage due to their inherent safety, low cost, and environmental friendliness. However, manganese dioxide (MnO₂)-based cathodes, which are widely studied for ZIBs owing to their high theoretical capacity and low cost, face severe capacity fading issues that hinder the commercialization of ZIBs. This performance degradation mainly stems from the weak van der Waals forces between MnO₂ layers leading to structural collapse during repeated Zn²⁺ insertion and extraction; it is also exacerbated by irreversible Mn dissolution via Mn³⁺ disproportionation that depletes active materials, and further aggravated by dynamic electrolyte pH fluctuations promoting insulating zinc hydroxide sulfate (ZHS) formation to block ion diffusion channels. To address these interconnected challenges, in this study, a synergistic strategy was developed combining crystal engineering and pH buffer regulation. We synthesized three MnO₂ polymorphs (α-, δ-, γ-MnO₂), identified δ-MnO₂ with flower-like microspheres as optimal, and introduced sodium dihydrogen phosphate (NaH₂PO₄) as a pH buffer (stabilizing pH at 2.8 ± 0.2). The modified electrolyte improved δ-MnO₂ wettability (contact angle of 17.8° in NaH₂PO₄-modified electrolyte vs. 26.1° in base electrolyte) and reduced charge transfer resistance (Rct = 78.17 Ω), enabling the optimized cathode to retain 117.25 mAh g⁻¹ (82.16% retention) after 2500 cycles at 1 A g⁻¹. This work provides an effective strategy for stable MnO₂-based ZIBs, promoting their application in renewable energy storage. Full article

Priapism is a frequent and debilitating complication in patients with sickle cell disease (SCD), characterized by recurrent ischemic episodes that can culminate in fibrosis of the erectile tissue and irreversible erectile dysfunction. Despite significant advancements in the management of acute episodes, current therapies remain largely ineffective in preventing recurrences, emphasizing the need for novel strategies that target the underlying pathophysiology. This narrative review describes the mechanistic links between oxidative stress and nitric oxide (NO) dysregulation in the pathogenesis of SCD-associated priapism, with a particular focus on the NO–cyclic guanosine monophosphate (cGMP)–phosphodiesterase type 5 (PDE5) signaling axis. We analyze preclinical evidence supporting resveratrol, a natural polyphenolic compound, as well as its NO-donor hybrid derivatives, as emerging therapeutic candidates. Additionally, we discuss the potential of combining resveratrol with current treatment approaches, and address the translational challenges that must be overcome to move from preclinical data to clinical application. Taken together, the evidence presented in this review supports resveratrol-based therapies as a promising approach for oxidative-stress-driven priapism in SCD and delineates critical perspectives for their further investigation. Full article

Anecdotal reports have recently circulated suggesting that intramuscular injection of bacteriostatic saline (BS)—which contains benzyl alcohol (BnOH)—can reverse botulinum toxin type A (BoNTA)-induced brow ptosis. Given the well-established intracellular persistence of BoNTA’s light chain and its irreversible cleavage of SNAP-25, such rapid functional recovery challenges existing pharmacological understanding. This study employed high-resolution pharmacokinetic/pharmacodynamic (PK/PD) modelling using the AesthetiSim™ platform to systematically evaluate this hypothesis. A total of 30,000 virtual patients were randomized to receive BoNTA alone, BoNTA followed by BS injection, or BoNTA followed by normal saline (NS) at Day 7. The model incorporated BoNTA diffusion, internalization, SNAP-25 cleavage, neuromuscular output, and transient BS effects on membrane permeability and endosomal trafficking. Simulated recovery trajectories were tracked over 90 days. The primary outcome, time to 80% restoration of baseline frontalis muscle force (T₈₀), averaged 42.0 days in the BoNTA-only group and 35.5 days in the BS group (Δ = −6.5 days; p < 0.001). Only 13.9% of BS-treated patients reached the T₈₀ threshold by Day 30. Partial reactivation (T₃₀) occurred earlier with BS (21.8 ± 5.3 days vs. 27.3 ± 4.9 days), and the area under the effect curve (AUEC) was increased by 9.7%, reflecting higher overall muscle function over time. In molecular simulations, BnOH produced a minor rightward shift in the BoNTA–SNAP-25 dissociation curve, but receptor occupancy remained above 90% at therapeutic toxin concentrations, suggesting no meaningful impairment of binding affinity. A global Sobol sensitivity analysis demonstrated that the primary driver of recovery kinetics was intracellular LC degradation (49% of T₈₀ variance), while BS-modulated extracellular parameters collectively contributed less than 20%. These findings indicate that BS does not reverse the molecular action of BoNTA but may transiently influence recovery kinetics via non-receptor-mediated pathways such as increased membrane permeability or altered vesicular trafficking. The magnitude and variability of this effect do not support the notion of a true pharmacologic reversal. Instead, these results emphasize the need for mechanistic scrutiny when evaluating rapid-reversal claims, particularly those propagated through anecdotal or social media channels without supporting biological plausibility. Full article

We here delve into the intricate and evolving concepts of brain death and consciousness, particularly at the end of life. We examine the historical and technological advancements that have influenced our understanding of death, such as mechanical ventilation and resuscitation techniques. These developments have challenged traditional definitions of death, leading to the concept of brain death, defined as the irreversible loss of all brain functions, including the brainstem. We emphasize that consciousness exists on a continuum, ranging from full alertness to deep coma and complete cessation of brain activity. It explores various disorders of consciousness, including coma, vegetative state, minimally conscious state, and locked-in syndrome, each with distinct characteristics and levels of awareness. Neuroimaging techniques, such as EEG, fMRI, and DTI, are highlighted for their crucial role in diagnosing and understanding disorders of consciousness. These techniques help to detect covert consciousness, assess brain activity, and predict recovery potential. The phenomenon of the “wave of death,” which includes a paradoxical surge in brain activity at the point of death, is also discussed. We address the challenges in defining and understanding both death and consciousness, calling for biologically grounded, ethically defensible, and culturally sensitive definitions. We advocate for standardized neuroimaging protocols, longitudinal studies, and the integration of artificial intelligence to improve diagnosis and treatment. In conclusion, the document underscores the importance of an integrated, evidence-based approach to understanding the gray zones between life and death, recognizing that consciousness and death are dynamic processes with both biological and experiential dimensions. Full article

We present a quantitative theory of contraction and expansion cycles within the Quantum Memory Matrix (QMM) cosmology. In this framework, spacetime consists of finite-capacity Hilbert cells that store quantum information. Each non-singular bounce adds a fixed increment of imprint entropy, defined as the cumulative quantum information written irreversibly into the matrix and distinct from coarse-grained thermodynamic entropy, thereby providing an intrinsic, monotonic cycle counter. By calibrating the geometry–information duality, inferring today’s cumulative imprint from CMB, BAO, chronometer, and large-scale-structure constraints, and integrating the modified Friedmann equations with imprint back-reaction, we find that the Universe has already completed $N_{\mathrm{past}}=3.6\pm 0.4$ cycles. The finite Hilbert capacity enforces an absolute ceiling: propagating the holographic write rate and accounting for instability channels implies only $N_{\mathrm{future}}=7.8\pm 1.6$ additional cycles before saturation halts further bounces. Integrating Kodama-vector proper time across all completed cycles yields a total cumulative age $t_{\mathrm{QMM}}=62.0\pm 2.5\mathrm{Gyr}$, compared to the $13.8\pm 0.2\mathrm{Gyr}$ of the current expansion usually described by $\mathrm{\Lambda }$CDM. The framework makes concrete, testable predictions: an enhanced faint-end UV luminosity function at $z\gtrsim 12$ observable with JWST, a stochastic gravitational-wave background with $f^{2/3}$ scaling in the LISA band from primordial black-hole mergers, and a nanohertz background with slope $\alpha \simeq 2/3$ accessible to pulsar-timing arrays. These signatures provide near-term opportunities to confirm, refine, or falsify the cyclical QMM chronology. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with curative surgical interventions feasible for a minority of patients. This review highlights recent advances in thermal (e.g., radiofrequency ablation, microwave ablation, and cryoablation) and nonthermal (e.g., ethanol ablation and irreversible electroporation) ablative modalities as curative-intent alternatives to surgery. Evolving applications of transcatheter intra-arterial radioembolization (TARE) with ablative dosimetry will be explored, and histotripsy, an emerging technology, will be introduced. Full article

Hearing loss affects millions and is often caused by irreversible damage to mechanosensory hair cells. Humans and other mammals lack the capacity to regenerate damaged hair cells; however zebrafish, Danio rerio, can regenerate hair cells that are present in the ear and mechanosensory neuromasts, making this animal an ideal model for understanding hair cell regenerative mechanisms. This study investigates the role of the GDP-fucose biosynthesis gene GDP-mannose 4,6-dehydratase (gmds) in regulating neuromast hair cell regeneration in zebrafish. Fucosylation is required for Notch signalling, a critical negative regulator of hair cell regeneration, and we therefore hypothesized that loss of gmds function would enhance hair cell regeneration. We demonstrate increased hair cell number in gmds mutants, and increased hair cell number following chemical ablation of hair cells with neomycin. Additionally, gmds mutants exhibited accelerated neuromast and hair cell regeneration, achieving complete restoration faster than wild-type siblings. Pharmacological inhibition of Notch signalling further enhanced hair cell regeneration in wild-type siblings but less so in gmds mutants, indicating that Notch signalling may partially regulate hair cell regeneration downstream of gmds. These findings highlight the importance of GDP-fucose biosynthesis in regulating hair cell number and regeneration, likely partially dependent on Notch signalling. Full article

The variational method holds considerable significance within mathematical and theoretical physics. Its importance stems from its capacity to characterise natural systems through physical quantities, irrespective of the chosen frame of reference. This characteristic makes it a powerful tool for understanding the behaviour of diverse physical phenomena. A global and statistical approach originating from the principles of non-equilibrium thermodynamics has been developed. This approach culminates in the principle of maximum entropy generation, specifically tailored for open systems. The principle itself arises as a direct consequence of applying the Lagrangian approach to open systems. The work focuses on a generalised method for deriving the thermodynamic Hamiltonian. This Hamiltonian is essential to the dynamical analysis of open systems, allowing for a detailed examination of their time evolution. The analysis suggests that irreversibility appears to be a fundamental process related to the evolution of states within open systems. Full article

Asthma is a chronic inflammatory disease with a heterogeneous course, often progressing silently from mild symptoms to severe, treatment-refractory disease. Current guidelines recommend biologic therapies after failure of high-dose inhaled corticosteroids and additional controllers, typically in patients with frequent exacerbations. This reactive approach may delay intervention until irreversible airway remodeling has occurred, limiting the potential benefits of biologic therapy. Therefore, severe asthma may be envisioned as the consequence of missed opportunities for early interventions. Early initiation of biologic therapy—guided by biomarkers such as blood eosinophil count and fractional exhaled nitric oxide (FeNO), as well as symptom burden and risk of lung function decline—may prevent progression to severe asthma and improve remission rates. This position paper advocates for a shift from severity-based to risk-based treatment strategies, recommending earlier biomarker assessment, redefinition of escalation criteria, and clinical trials designed to evaluate biologics in symptomatic non-exacerbating patients. By recognizing persistent inflammation and progression risk earlier in the disease course, clinicians may have a critical opportunity to alter the trajectory of asthma, reduce long-term morbidity, and achieve sustained control before irreversible damage occurs. Full article