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The quest for high-energy-density batteries has spurred interest in multielectron chemistry beyond conventional two-electron reactions. Here, we report a cascade battery that synergistically integrates gas-phase (Cl2 ↔ Cl-), liquid-phase (Cu2+ ↔ Cu+), and solid-phase (S ↔ CuS ↔ Cu2S) redox reactions within a deep eutectic solvent (DES) electrolyte. This unique gas-liquid-solid triphase coupling strategy unlocks a seven-electron transfer process. In particular, the chloride-rich DES electrolyte fundamentally alters the copper (Cu) redox thermodynamics, enabling a reversible liquid-phase Cu2+/Cu+ couple via the formation of stable [CuCl3]2- complexes, which prevents disproportionation. The resulting cascade cell delivers an ultrahigh specific capacity of 4426.4 milliampere hours per gram [based on sulfur (S)] and exceptional cycling stability (88.5% capacity retention after 2000 cycles at 10 C). Furthermore, a practical pouch cell configuration achieves a high operating voltage of 1.5 volts and a remarkable energy density of 6917 watt-hours per kilogram (based on S; 2767 watt-hours per kilogram based on the total mass of the cathode), substantially surpassing most aqueous S-based systems. Ultimately, this work underscores that the strategic integration of orchestrated gas-liquid-solid triphase chemistry transcends the capacity limits of conventional single-phase reactions, demonstrating a viable pathway toward a next-generation paradigm for ultrahigh-energy-density storage.

An acyclic alkyl-imino phosphenium cation stabilized by an N-heterocyclic imine is reported, revealing how scaffold modification unlocks reactivity inaccessible to classical phosphenium platforms. The cation displays pronounced Lewis acidity, amphiphilic cycloaddition reactivity, and N-H bond oxidative addition-like reactivity that is unprecedented for acyclic phosphenium platforms. These findings demonstrate that strategic modification of the phosphenium scaffold enables new modes of bond activation, expanding on the reactivity of acyclic phosphenium cations.

Thiazole heterocycles, characterized by their unique combination of sulfur and nitrogen atoms, have emerged as versatile scaffolds in medicinal chemistry. The presence of heteroatoms provide multiple binding sites, enabling rapid investigation of structure activity relationships (SARs), aiding the development of potent, and targeted inhibitors. Thiazoles exhibit remarkable tolerance to diverse functionalities, and can be readily modified to fine-tune lipophilicity, polarity, and metabolic stability, making thiazoles as valuable frameworks for hit-to-lead optimization, and drug development with favorable pharmacokinetic profiles. In this context, the current review (2020-2025) highlights: biologically inspired thiazoles, and approved drugs, synthetic approaches like condensation, multicomponent reactions, microwave-assisted synthesis, and cycloaddition strategies, recent advances in anti-oxidant, and antidiabetic thiazole analogues, analysis of SARs, and molecular docking insights into protein-ligand interactions. Thus, biological screenings reveal thiazole hybrids often outperform simple thiazoles, with several analogues demonstrating superior anti-oxidant and antidiabetic potential to drugs in free radical scavenging and enzymes inhibition assays. SARs analysis confirm electron-donating and electron-withdrawing groups around thiazole ring significantly influence inhibitory potential of the screened analogues. Molecular docking further supports these findings, showing strong intermolecular interactions that underpin enhanced bioactivity. To conclude, thiazole scaffolds represent a promising frontier in rational drug design, and discovery. Thus, the present review article emphasizes continued exploration through optimized synthetic methodologies, hybrid development, and comprehensive biological evaluation to unlock their full therapeutic potential.

Electrolytic hydrogen production is constrained by freshwater scarcity and the spatial mismatch between renewable energy resources and water availability. Direct municipal reclaimed water (MRW) electrolysis offers a sustainable route by producing hydrogen while reusing co-produced oxygen for wastewater aeration. Here, we show that MRW electrolysis under industrially relevant conditions achieves hydrogen purity and Faradaic efficiency comparable to deionized water electrolysis, yet requires higher energy input. Systematic evaluation of water matrix constituents identifies calcium-induced oxygen evolution reaction (OER) inhibition as the dominant bottleneck, while the hydrogen evolution reaction remains largely unaffected. Distinct from the conventional focus on Ca/Mg induced cathodic scaling and mass-transfer blockage, our results reveal a previously unrecognized anodic calcium-specific inhibition mechanism that directly limits OER activity. Integrated experimental and theoretical analyses demonstrate that preferential Ca2+ adsorption perturbs the local electronic structure of the electrode, alters OER intermediates, reduces the affinity of active sites for hydroxide ions, and ultimately impedes oxygen evolution. Given the widespread presence of Ca2+ in low-grade water sources, this anodic inhibition mechanism represents a critical yet overlooked constraint for direct water electrolysis beyond conventional cathodic scaling. These findings emphasize the need to consider Ca2+ tolerance in anode design and provide guidance for developing durable, impurity-tolerant electrolysis systems.

The integration of light polarization into non-volatile memory enables angle-resolved information processing, unlocking new photonic channels for communication, computation and imaging. Yet practical polarization-sensitive memory remains rare. Here, we report a 2D rhenium disulfide (ReS2)/hafnium zirconium oxide (Hf0.5Zr0.5O2, HZO) ferroelectric field-effect transistor in which field-driven charge separation realizes polarization-resolved memory. The redistribution of photo-generated carriers at the heterostructure interface establishes an interfacial electrostatic field that modulates HZO ferroelectric domains and encodes non-volatile states. We also find that interfacial compressive stress induced by lattice mismatch shortens the Re-Re bond, which enhances the Re-Re chain anisotropy by 3.7x (from 2.67 to 9.98). Integrated into arrays for photonic neural networks, the device attains >93% accuracy on a transformer model. Leveraging the cumulative switching property of HZO with sequential optical signals, the device enables in-situ multiplication and accumulation of inputs over time, achieving 4x area saving with <1% accuracy loss. Beyond amplitude and phase, the demonstrated electro-optic device enables optical polarization as an additional information read-out, which significantly increases the information density of photonic-based computing.

The application of the novel KRASG12D inhibitor in pancreatic ductal adenocarcinoma (PDAC) is currently hindered by adaptive resistance. Metabolic reprogramming is a hallmark of KRASG12D signalling, yet the mechanisms linking these alterations to immunosuppression and low therapeutic response are poorly defined. To identify the key regulatory nodes connecting KRASG12D-driven metabolic adaptations to tumour microenvironment and develop a mechanistic-based combinatorial strategy. We integrated whole-exome sequencing, untargeted metabolomics and single-cell RNA sequencing of human PDAC specimens to analyse the metabolic-immune landscape. We evaluated therapeutic efficacy using the autochthonous mouse and patient-derived xenograft models. We found that KRASG12D enhanced cholesterol metabolism and promoted CD8+ T cell exhaustion, whereas KRASG12D inhibition or cholesterol synthesis blockade induced compensatory ULK1-associated autophagy. Cotargeting cholesterol metabolism and autophagy potentiated the antitumour efficacy of the KRASG12D inhibitor MRTX1133 and alleviated CD8+ T cell exhaustion. Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival. Genetic depletion or pharmacological inhibition of USP20 with GSK2643943A suppressed these pathways and restored CD8+ T cell function, improving responses to MRTX1133 and anti-programmed cell death protein-1 (anti-PD-1). In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression. USP20 acts as a critical metabolic checkpoint that orchestrates CD8+ T cell exhaustion and therapeutic response. Targeting the USP20-cholesterol-autophagy axis represents a promising strategy to reverse immune suppression and unlock the full potential of KRASG12D inhibitors in PDAC.

Ruminant milk-borne extracellular vesicles (EVs) have garnered significant attention as assorted bioactive components of intercellular communication and key regulators of both physiological and stressful conditions. These membrane-bound vesicles transport diverse molecular cargo, contributing to immune modulation, cellular homeostasis, metabolic and stress regulation. These distinctive characteristics of EVs position them as potential indicators of physiological and disease conditions in both human and animal research. Further, thermal stress induced alterations in the biological system of the animal are mirrored in these milk-borne molecular structures, indicating them to be accessible, non-invasive markers of heat stress in ruminant livestock. However, a holistic comprehension of the role of ruminant milk-derived EVs in human and livestock health remains limited. In spite of rapid developments in this field, variability in methodologies, investigations and stated findings demands a comprehensive synthesis of existing knowledge. In this context, this work offers a systematic review of the aspects of ruminant milk-derived EV's isolation, function, cargo profiling, biomarker prospects and potential applications. Relevant articles were screened based on predefined inclusion criteria to identify significant research trends and thematic areas. A total of 124 studies published between 1990 and January 2026 were examined using Scopus&#xae; data, following the structured search using the keywords "extracellular vesicle" AND milk, combined with additional terms including "heat stress," "cell culture," "buffalo," "cattle," "sheep," and "goat." Descriptive statistics, along with text mining and topic analysis, were performed. Publications on ruminant milk-derived EVs began in 2012, with marked increase after 2021 and significant peak in 2024 with majority of publications in the International Journal of Molecular Sciences and Journal of Dairy Science. Major proportion of publications originated from China followed by the United States, Australia, Italy and Japan. The most frequent co-occurring terms were "extracellular vesicle," "milk," "exosomes," "bovine milk" and "drug delivery." Text mining results indicated strong research focus on ruminant milk-derived EVs in the context of biomedicine, nutraceuticals and human health compared with the diminished concentration on livestock research aspects like heat stress. The 7 identified topics following topic analysis spanned distinct subjects including ruminant milk EV isolation, characterization, functioning, immune-modulatory role and applications. The analysis also revealed significant challenges in method standardization, characterization protocols clinical validation and supportive regulatory frameworks. Research skew toward miRNA, overlooking other biomolecules was acknowledged; amidst EVs applications in livestock, especially under climate stress, remaining unventured. Further, key gaps in toxicity, safety and bioavailability was also identified demanding inter-disciplinary collaboration for diagnostic and therapeutic deployment across species. Bridging these gaps remains crucial for unlocking the maximum potential of ruminant milk-borne EVs in advancing the One Health framework and for the attainment of sustainable development goals.

Traditional and indigenous medical systems have a long history of using medicinal plants to treat conditions now understood as chronic inflammation. This ethnopharmacological knowledge provides a rich resource for discovering novel anti-inflammatory agents. This review critically evaluates the evidence for the modulation of the Receptor for Advanced Glycation End-products (RAGE) signaling pathway by natural products derived from traditional medicines, aiming to connect this traditional knowledge with modern molecular pharmacology. A comprehensive literature review was performed using the PubMed database. The search focused on keywords such as "RAGE," "natural products," and "traditional medicine" to identify studies detailing the mechanistic interactions between natural compounds and the RAGE pathway. Natural products, including polyphenols, terpenoids, and alkaloids, modulate the RAGE axis through several key mechanisms: (1) inhibiting the formation of Advanced Glycation End-products (AGEs); (2) directly blocking the RAGE-ligand interaction; (3) downregulating RAGE expression; and (4) suppressing downstream inflammatory signaling. Compounds like quercetin, ursolic acid, and berberine have demonstrated significant activity in various preclinical models. Natural products represent a profound source of multi-target RAGE modulators, offering a potential therapeutic advantage over synthetic single-target drugs. While challenges in bioavailability and clinical translation remain, the data strongly validates the ethnopharmacological approach. Future progress depends on integrating this traditional wisdom with modern technologies to unlock the full clinical potential of these compounds.

Azulene, a nonbenzenoid aromatic isomer of naphthalene with exceptional optoelectronic properties, has long eluded general methods for selective functionalization, especially on its electron-deficient seven-membered ring. Here, we overcome this limitation by introducing the first practical precursors to azulyne intermediates. In stark contrast to well-established benzyne chemistry, the synthesis of these azulyne precursors is far from trivial, demanding tailored strategies to construct their bicyclic frameworks. Computations reveal that 5,6- and 4,5-azulyne possess substantial yet manageable ring strain and marked electrophilicity. Leveraging these versatile intermediates, we develop a modular platform that enables direct, efficient, and site-selective incorporation of diverse functionalities onto the azulene core through cycloadditions, nucleophilic additions, &#x3c3;-bond insertions, and transition-metal-catalyzed reactions. This strategy grants unprecedented access to a wide range of polysubstituted azulenes and complex azulene-embedded polycyclic aromatic compounds (PACs), with regioselectivity governed by predictable steric and electronic principles. Our work transforms azulene from a synthetically challenging motif into a programmable building block based on this unique nonalternant architecture.

Photoswitches provide the opportunity to remotely and precisely control matter on the nanoscopic scale. For many materials and biological applications, photoswitches with long wavelength response are essential; however, few switches offer inherent response to red/near infra-red light. Previous works have described the use of intermolecular interactions as a method to redshift the activation wavelength of photoswitches and to improve thermal half-life. However, these systems are limited in their application due to the inherent bimolecularity of this strategy preventing its use in dilute or complex environments. Herein, we describe the use of topologically constrained supramolecular interactions to improve the switching properties of an indigo photoswitch within a [2]-rotaxane. This enabled photoswitching with 730&#xa0;nm light, as well as a 100-fold increase in thermal half-life and double the population of the metastable state under constant irradiation. This surpasses previous attempts at using supramolecular interactions to increase the thermal half-life by >10-fold. This novel strategy towards the redshifting and fine-tuning of these molecular photoswitches has implications for the design of molecular machines and applied switching technologies. We anticipate that our insights into the design of such molecules will unlock new applications for mechanically interlocked molecules.

High-dimensional photonic entanglement holds substantial promise for advancing quantum communication, computation, and metrology. For example, large-alphabet quantum communication protocols are known to benefit from enhanced noise resilience and information capacity via multibit time-bin encoding. Yet, characterizing high-dimensional entangled states is challenging, as full-state tomography becomes prohibitively costly and often requires unrealizable measurements. Here, we demonstrate a scan-free method to characterize high-dimensional entanglement in the time-frequency domain. Our reconstruction achieves a record 5.70&#xa0;&#xb1;&#xa0;0.07 ebits and a fidelity of 65.4&#xa0;&#xb1;&#xa0;0.4% with the maximally entangled state of local dimension 1021, certifying the presence of 668-dimensional entanglement. We further prove the attainability of a secure key rate of 15.6 kilobits per second in a composable finite-size, entanglement-based protocol and show that in continuous operation, the setup can quickly approach asymptotic key rates. Using commercial telecom components and state-of-the-art low-jitter single-photon detectors, our scalable architecture offers a practical path toward high-rate, noise-resilient quantum communication test beds.

This chapter summarizes the current knowledge on the practical, methodological, and interpretative aspects of applying metaproteomics in water biotechnology. We outline the full metaproteomic workflow-from sampling and protein extraction to LC-MS/MS acquisition, database construction, quantitative analysis, and bioinformatic interpretation-and emphasize critical considerations specific to complex matrices such as EPS-rich biofilms, granular sludge, and low-biomass drinking water. Case studies illustrate how metaproteomics can clarify mechanisms of micropollutant degradation, nitrogen-transforming pathways, biofilm functional architecture, and microbial resilience under operational stress. Recent advances in data-independent acquisition, metagenome-informed databases, and integrative multi-omics are shown to substantially improve depth, reproducibility, and functional resolution. Finally, we discuss emerging applications in wastewater-based epidemiology, where metaproteomics complement nucleic-acid-based surveillance by enabling the detection of large biomolecule biomarkers of population health and industrial activity. Although metaproteomics is already being applied across a wide range of water cycle contexts and is producing promising, robust results, several challenges, including limitations in analytical chemistry, database completeness, and bioinformatics workflows, continue to hinder its broader implementation. Continued technical research and innovation are therefore essential to fully unlock its potential in water biotechnology.

Polyamines are essential ubiquitous polycationic molecules involved in diverse cellular processes ranging from gene expression to cell growth and differentiation. The dysregulation of these genes is linked to cancer and neurological disorders. SLC45A4, a recently emerged selective neuronal polyamine transporter, is a critical mediator of polyamine homeostasis and is further linked to pain sensitivity. However, the molecular mechanism underlying substrate recognition and transport remains poorly understood. Here, we present a comprehensive atomistic investigation of SLC45A4 alone and interactions with three major polyamines. We employ knowledge-guided molecular docking and all-atom molecular dynamics simulations in lipid mimetic bilayers at &#x3bc;-seconds time scale to model the binding modes of spermidine, spermine, and putrescine to SLC45A4. Our results reveal a substrate-dependent landscape in which high-affinity putrescine maintains structural fidelity, whereas long spermine triggers conformational expansions through allosteric decoupling and plug domain unwinding. Furthermore, we identified a conserved cholesterol motif i.e., Leu104, Leu114 and Ala125 which acts as an allosteric splint to stabilize the transporter, demonstrating that a realistic lipid environment is essential to unlock functional dynamics restricted by detergent micelles. Further, the dynamic differences between detergent-solubilized and nanodisc-embedded systems explored herein highlight the micellar cage effect, demonstrating that realistic membrane simulations are essential for capturing MFS alternating-access motions and establishing a structural framework for SLC45A4 drug discovery. These results provide an atomic-level model for polyamine recognition and uptake by SLC45A4, thus provides new avenues for developing new pain therapies.

[This corrects the article DOI: 10.3389/fmicb.2025.1682456.].

The COVID-19 pandemic further emphasized the global demand for heparin and its expanding clinical relevance, indicating that even one of the oldest drugs in medicine continues to reveal new therapeutic horizons. Traditionally recognized for its anticoagulant and antithrombotic activities, heparin is increasingly being explored for its versatile therapeutic potential in the treatment of a range of pulmonary diseases, including respiratory infections (e.g. COVID-19), Acute Respiratory Distress Syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. In all of these diseases, inhaled unfractionated heparin (UFH) therapy has been investigated in a number of clinical trials that have demonstrated promise for this drug when administered directly to the lungs. However, using heparin by this "off label" route of administration, poses a number of technical challenges: the physicochemical properties of heparin at therapeutic doses often results in highly viscous formulations, causing device blockage and drug sorption during nebulization. These limitations underscore the need for innovative formulation strategies to improve aerosol flow, reduce dosing inefficiencies, and enable reliable pulmonary administration. Advancing heparin formulations for delivery to the lung could therefore unlock significant benefits for a wide spectrum of respiratory disorders, marking a new chapter in the long medical history of this drug as discussed below.

Regulated cell death (RCD) encompasses diverse forms induced by common cellular stressors, including oxidative stress and endoplasmic reticulum stress. Cells may display features from multiple RCD types, implying coexistence of "pure" and "mixed" forms of cell death. Ferroptosis is an iron-dependent form of RCD characterized by lipid peroxide accumulation and absence of specific biomarkers. Its regulation is heterogeneous and pathway-dependent, reflecting the broader complexity of the RCD spectrum. This study hypothesized two major regulatory pathways governing ferroptosis induction and functioning. The first pathway operates through GPX4, a central enzyme preventing ferroptosis by reducing lipid peroxides. Genetic GPX4 knockout and chemical GPX4 inhibition with ML210 resulted in significant upregulation of mevalonate pathway regulators SREBF1 and SREBF2, indicating compensatory anti-ferroptotic activation through the mevalonate pathway. The second pathway functions through the Xc&#x207b;/GSH system critical for glutathione synthesis. System Xc&#x207b; inhibition leads to intracellular cysteine depletion with subsequent glutathione depletion, inducing ferroptotic cell death. SREBF transcription factor cascades were downregulated in system Xc&#x207b;/GSH depletion experiments, contrasting with GPX4 inhibition responses. Instead, the system Xc&#x207b;/GSH pathway is primarily governed by ATF4 to maintain cystine uptake and glutathione biosynthesis under stress conditions. These findings confirm ferroptosis as a heterogeneous spectrum of cell death with multiple interacting yet mechanistically distinct pathways. Moreover, these data provide a dynamic multi-omics resource for further ferroptosis research.

Clinical genetic testing is now the standard of care for cardiomyopathy, guiding risk stratification, clinical management, and earlier diagnosis in family members. Yet, a large proportion of the genetic basis of cardiomyopathy remains incompletely explained. Prior efforts to identify genetic causes of cardiomyopathy have largely focused on coding DNA sequence, which accounts for only 3% of the human genome, leaving the noncoding regulatory sequence space relatively unexplored. A confluence of emerging technologies is now transforming our capability to identify and interpret noncoding variants. This review summarizes the field's current knowledge of how noncoding variants influence the development of cardiomyopathy, both from the standpoint of rare Mendelian disease variants and population-level risk alleles. In addition, we describe how new technologies have enabled systematic identification and prioritization of regulatory regions that govern gene expression. Beyond identification of regulatory regions, we discuss how causal testing of variants is now possible at an unprecedented scale through massively parallel reporter assays, allowing both detailed mapping of these regions and efficient validation of variants discovered through genome-wide association studies. Finally, we review deep learning approaches that hold the potential for genome-wide noncoding variant interpretation. Together, this review highlights strategies for large-scale interpretation of noncoding variants while also demonstrating the clear need for extension of clinical variant adjudication workflows to the noncoding genome to fully take advantage of increasingly available whole-genome sequencing data.

Mobile devices enable individuals to efficiently and effectively complete instrumental activities of daily living (IADLs), and independence in IADLs is associated with a positive quality of life (QOL). While there may be barriers to adults with acquired communication disorders learning to use these tools, research supports their capability to do so successfully given proper support. Speech-language pathologists (SLPs) are qualified to deliver mobile device instruction given their unique skill sets in working with individuals with cognitive-linguistic, behavioral, sensory, and physical barriers. We present three case studies of individuals with acquired communication disorders after their participation in a specialty graduate student clinic focused on individualized mobile device training. Client records were examined retrospectively to investigate the impact of such training on independence in IADLs and QOL. The results of this endeavor resulted in positive outcomes in IADL completion and QOL across all participants. SLPs and related professionals are urged to incorporate mobile device instruction into their treatments when addressing client goals.

Voltage-controlled ion insertion provides a powerful strategy for the analog tuning of material properties, enabling adaptive devices such as neuromorphic transistors and smart displays. Among tunable materials, mixed ionic-electronic conducting oxides undergoing topotactic phase transitions are particularly compelling due to their dramatic property changes between fully oxidized and fully reduced states. However, intermediate oxidation states remain largely underexplored because of significant control limitations. In this work, we investigate the topotactic phase transition in strontium ferrite (SrFeO3-&#x3b4;) thin films by progressively and precisely modulating and quantifying oxygen non-stoichiometry via solid-state electrochemical pumping. This fine-tuning approach unveils the co-existence of multiple stable phases in equilibrium configurations across a broad range of oxidation states. A crystallographic mixing model that captures the structural-electronic coupling underlying this phenomenon is proposed, complemented by a defect chemistry framework that quantitatively describes the oxidation mechanism under applied voltage. These findings highlight the critical role of intermediate states in governing functional properties and open new pathways for designing advanced ionotronic oxygen-responsive devices.