High-entropy catalysts (HECs), including high-entropy alloys and high-entropy oxides, have emerged as a transformative class of catalytic materials owing to their exceptional compositional flexibility and entropy-stabilized structures. Unlike conventional catalysts, HECs possess a broad distribution of atomic configurations of surface-active sites that enable simultaneous modulation of reactants'/intermediates' adsorption and stabilization energetics, charge transfer, and reaction pathways. Such characteristics provide unique opportunities to overcome long-standing activity-selectivity-stability trade-offs in heterogeneous catalysis. Nevertheless, the extreme compositional complexity of HECs also creates major challenges in identifying the true catalytic active sites and elucidating the underlying reaction mechanisms. This review provides a perspective on how metal active-site engineering in HECs, including strain, ensemble effects, defect engineering, and dynamic surface reconstruction, regulates adsorption configurations, intermediate evolution, proton-coupled electron transfer, and catalytic pathway selectivity. By addressing knowledge gaps in the structure-activity relationship of high-entropy catalysts, this review aims to open a potential avenue for the translation of HEAs into practical implementations for a sustainable energy and environmental future.

Patients living with cancer now account for a substantial and growing share of emergency department (ED) visits and carry a high burden of hospitalization and in-hospital death. Their acute presentations are frequently multifactorial - driven by disease progression, treatment toxicity, immunosuppression, or the decompensation of comorbid conditions. They may present with higher rates of complications because of novel therapies, such as immune checkpoint inhibitors and cellular therapies, whose emergency manifestations remain unfamiliar to many emergency physicians. Despite this growing importance, the unscheduled care of patients with cancer has received comparatively little dedicated research. How these patients are managed in the ED, how often the emergency physician can access the oncology medical record and goals of care, how the acute complications of new anticancer therapies present, and how a background of cancer should modify the diagnostic approach to everyday emergencies remain poorly characterized. To address these gaps, the Cohort of Onco-hematologic patients visiting the Emergency depaRtment was designed as a prospective, multicenter French cohort of consecutive adults with active cancer or in remission for less than 1 year, presenting to the ED for any reason. Enrollment took place across a national network of 76 EDs for two 1-week periods (summer 2025 and winter 2025-2026), with follow-up to 90 days, yielding a large sample of patients designed as a platform for multiple analyses. The primary aim of Cohort of Onco-hematologic patients visiting the Emergency depaRtment is to determine whether being managed in an ED located within the patient's own cancer referral center, rather than any other hospital, is associated with improvement in morbidity and mortality, captured by the number of days alive and out of hospital at 30 days. Beyond this primary aim, the cohort will support a broad research program on the place of the ED in the cancer care pathway, from patient profiling and pathway description to the emergency toxicities of anticancer drugs and the cancer-specific features of common presentations.

The two-electron oxygen reduction reaction (2e- ORR) for H2O2 production and the subsequent in situ activation to ·OH are constrained by linear scaling relationships, making it difficult for a single active site to simultaneously optimize O2 activation and H2O2 conversion. This work overcomes the trade-off by spatially decoupling the cascade reaction onto single-atom and cluster-hybrid sites and employing photoelectrocatalysis (PEC). Through a ligand-exchange and pyrolysis route derived from a metal-organic framework precursor, Bi single atoms and clusters are co-anchored on B-doped TiO2. The hybrid interface thermodynamically optimizes the intermediate adsorption energies to ensure cascade selectivity, whereas PEC kinetically accelerates the H2O2-to-·OH conversion by supplying photogenerated electrons. Density functional theory and free-energy diagrams indicate that H2O2 forms at the single atoms and dissociates into ·OH at the clusters, with the relationship between the p-band center and ·OH yield following the Sabatier principle. The catalyst delivers a ·OH production rate of 250 µM h-1 at neutral pH and remains active over a broad pH range (3-9). Moreover, it enables broad-spectrum removal of recalcitrant organic pollutants and retains stable performance over 50 h of operation in a flow-cell reactor. This work offers guidance for designing cascade catalysts at single-atom and cluster-hybrid interfaces.

Tumor cells maintain abnormal metabolism to support their rapid proliferation, which often compromises the therapeutic outcomes, including pyroptosis. Inhibiting the copper transporter ATPase (ATP7A) effectively disrupts this metabolic balance, yet current exogenous ATP7A inhibition strategies suffer from poor delivery efficiency and low tumor selectivity. Herein, we developed an endogenous regulation strategy to downregulate ATP7A levels using a self-amplifying bio-clay enzyme (Bio-Clayzyme), cupriferous Prussian blue/montmorillonite (CuPB/Mt). Upon tumor cell internalization, CuPB/Mt induces a robust reactive oxygen species (ROS) storm, accompanied by antioxidant depletion, mitochondrial dysfunction, and adenosine triphosphate (ATP) exhaustion. These metabolic disturbances are associated with reduced ATP7A expression, which may subsequently impair ATP7A-mediated copper efflux. The resulting intracellular copper accumulation may further promote ROS amplification, supporting a positive feedback loop among ROS production, ATP7A downregulation, and copper retention. Specifically, the introduction of Mt optimizes the Cu d-band center and strengthens tumor cell adhesion, thereby boosting the multi-enzyme-like catalytic activity and enabling efficient utilization of short-lived ROS. Consequently, CuPB/Mt activates nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3)-dependent pyroptosis and elicits a potent anti-tumor immune response, offering an ATP7A-mediated endogenous regulatory paradigm for self-amplified catalytic therapy and immunogenic pyroptosis.

Proteases must be tightly regulated to prevent uncontrolled degradation, yet the mechanisms ensuring such control remain poorly understood. Members of the widespread M48 metalloprotease family are kept inactive by an autoinhibitory plug that blocks catalytic water activation, but how this plug is released remained elusive. Here, using genetic, biochemical and cryo-EM approaches, we discover the activation mechanism of BepA, a quality-control protease that preserves outer membrane integrity by surveilling the β-barrel assembly machinery (BAM) in Gram-negative bacteria. Our cryo-EM analysis of BepA engaged with a stalled BAM-substrate assembly complex revealed that a flexible, unstructured α6-lid covering the active site in the latent protein functions as a molecular harpoon, inserting into the outer membrane when a substrate stalls at BAM and thereby docking BepA at the complex. This membrane anchoring promotes displacement of the autoinhibitory plug and unlocks protease activity precisely where and when it is needed. Thus, a dual enzyme activation mechanism is coupled to membrane association under stress, ensuring that BepA remains inactive until properly localized. Our findings reveal how membranes themselves can license protease activation, a principle that may extend beyond M48 metalloproteases.

Knee osteoarthritis (KOA) is a degenerative joint disease primarily driven by the disruption of homeostasis in the chondrocyte extracellular matrix (CECM). This review systematically examines the central role of CECM homeostasis in KOA pathogenesis and summarizes recent advances in this field. We synthesized contemporary basic and clinical research to analyse the mechanisms underlying CECM homeostatic imbalance. These include biomechanical stress, inflammatory responses, programmed cell death (e.g., apoptosis, pyroptosis, ferroptosis), impaired autophagy, and cellular senescence. We also evaluated intrinsic risk factors and the application of related biomarkers for diagnosis and prognosis. Our analysis identifies multifaceted pathways driving CECM imbalance and highlights promising multi-modal therapeutic strategies. These include novel pharmacological agents (e.g., high-purity chondroitin sulphate, natural active monomers), physical and regenerative therapies (e.g., stem cells, platelet-rich plasma), precision interventions (e.g., gene editing, RNA interference), and tissue engineering approaches (e.g., smart biomaterials, biomimetic scaffolds). The evidence demonstrates that these strategies can effectively modulate CECM metabolism, promote cartilage repair, and slow disease progression. Targeting CECM homeostasis is a core strategy for developing disease-modifying therapies for KOA. Future efforts should focus on interdisciplinary integration, individualized precision medicine, and multi-site synergistic interventions. This review provides a comprehensive foundation for innovating strategies to delay or reverse KOA progression by restoring CECM balance.

RAS proteins (HRAS, KRAS, NRAS) contribute to many physiological signal transduction pathways involving cell growth, cell division, and survival. RAS proteins possess GTPase activity. These proteins toggle between inactive and active forms; the conversion of inactive RAS-GDP to active RAS-GTP is facilitated by guanine nucleotide exchange factors (GEFs) turning the switch on and the intrinsic RAS-GTPase activity accelerated by the GTPase activating proteins (GAPs) turning the switch off. RAS is the upstream component of the RAS-RAF-MEK-ERK and the PI3-kinase-AKT signaling cascades. One-fifth of all cancers bear RAS mutations and about 75% of them involve KRAS. Except for the GTP/GDP binding site, RAS proteins lack deep surface pockets able to bind high-affinity inhibitors, which impeded the development of specific antagonists. KRAS mutations occur frequently in pancreatic, lung, and colorectal cancers, which are among the deadliest cancers worldwide. RAS mutations include those of codon 12 G12D/V/C/R, codon 13 G13D, and codon 61 Q61R/K/L. Studies conducted over the last 15 years led to the discovery of the so-called RAS switch II pocket. Sotorasib and adagrasib, which interact with this pocket and directly block the action of KRAS following the covalent modification of KRAS C12, are FDA-approved for the second-line treatment of KRASG12C-mutant non-small cell lung cancer. Daraxonrasib, which is an indirect inhibitor of wildtype and mutant H/K/NRAS isoforms, is FDA approved for the second-line treatment of all RAS-mutant pancreatic cancers. Daraxonrasib first forms a complex with cyclophilin A (a chaperone protein), which then interacts with active RAS to block RAS signaling.

One of the main challenges in understanding the fate and impacts of pesticides is to incorporate multiple environmental and human matrices and their interrelations. This study aimed to identify the most critical substances through detection frequency (DF) analysis of multiple environmental and biological matrices of Swiss study site containing orchards. A sampling campaign was conducted during the harvest season of 2021 that encompassed conventional and organic farming systems (FS), and 3 population groups (farmers, neighbors, and consumers). We analyzed 208 pesticide residues (active substances and metabolites) in a total of 62 environmental samples (soil, plant, indoor dust, water, and sediment) and 235 human samples (urine, feces, plasma, and wristbands). DDE p,p' was the substance with the highest DF in environmental samples (61%), followed by dicamba (55%), hexachlorobenzene (52%), difenoconazole (44%), and dieldrin (42%). For humans, 8 of the 20 most frequently detected substances are highly hazardous and 9 are probably hazardous to human health. Among the 6 substances detected in human blood, 2 are hazardous (piperonyl butoxide and hexachlorobenzene) and 2 are probably hazardous (fluopyram and DDE p,p'). Samples from organic FS are less contaminated than samples from conventional systems. Conventional farmers showed the highest DFs for several pesticide residues. 25% of compounds including banned substances detected in both compartments illustrates how legacy contaminants continue to dominate in the mixtures and circulate between environmental reservoirs and humans. Integrating pesticide insights from diverse matrices is crucial to advancing our understanding of pesticide exposure and designing more effective risk reduction strategies.

Methionine sulfoxide reductase A (MsrA) protects proteins from oxidative damage through cysteine-based redox cycling, but how mammalian MsrA is structurally regulated during oxidation and reductive recycling has remained unclear. We report three crystal structures of mouse MsrA (mMsrA) that capture distinct redox states - reduced (3.0 Å), BME-trapped intermediate-like (BTIL; 1.6 Å), and oxidized (1.9 Å) - and reveal an unrecognized layer of regulation centered on Cys107. The BTIL structure visualizes catalytic Cys72 as a mixed disulfide with β-mercaptoethanol (BME) alongside a sulfenic acid at Cys107, a configuration not previously observed. The oxidized structure resolves the canonical Cys72-Cys218 disulfide together with an unexpected Cys107-Cys227 pairing that locks a C-terminal loop into a cap over the active site. LC-MS/MS mapping, MD simulations, activity assays, and thioredoxin (Trx)-trapping experiments converge on a model in which Cys72 drives catalysis, while Cys107-mediated disulfide rearrangement and Cys227-directed Trx entry gate substrate access and enzymatic regeneration - defining a noncanonical oxidized state that expands the mechanistic repertoire of mammalian MsrA under oxidative stress.

Active biomonitoring using caged organisms is increasingly applied to assess chemical contamination and toxicity in aquatic environments. In France, caged Gammarus fossarum is routinely used to monitor bioavailable contamination in accordance with the European Water Framework Directive (WFD). Building on the approach initially proposed by Besse et al., who developed a method to define regional Bioavailable Background Assessment Concentrations (BBACs) for approximately 30 chemical compounds, this study aimed to establish BBAC thresholds at the national scale for the maximum number of compounds analyzed in caged gammarids by the six French water agencies. The BBAC represents the concentration above which contamination is interpreted as resulting from anthropogenic and/or geochemical sources, and below which it reflects background conditions. Using data from the 2019 nationwide monitoring campaign, encompassing 221 sites and 478 deployments, we determined BBAC values to distinguish natural background contamination from anthropogenic inputs and proposed contamination severity classes to characterize the intensity of site contamination. Among 250 compounds analyzed, 60 met BBAC determination criteria, including metals, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), perfluorooctanoate (PFOS), and certain herbicides. Contamination severity levels were set for 40 substances, enabling the classification of sites based on bioaccumulation levels for each contaminant. Applying such contamination thresholds facilitated a nuanced interpretation of contamination levels. This study represents the first large-scale application of caged gammarids across metropolitan French rivers for chemical biomonitoring in European continental waters. The BBAC values and contamination severity levels established here provide essential tools for regulatory agencies to assess contamination and support water quality management. These findings highlight the relevance of active biomonitoring with caged gammarids as a robust and standardized approach for monitoring chemical contamination in freshwater ecosystems.

Vitiligo is an acquired depigmenting disorder characterized by destruction of epidermal melanocytes and skin depigmentation. Although treatments have developed substantially, there is still a considerable proportion of vitiligo patients fail to achieve satisfactory repigmentation or experience disease recurrence after treatment withdrawal. Vitiligo treatment failure involves heterogeneous clinical states, including persistent disease activity, treatment resistance, site-related limitations, and disease recurrence. Importantly, refractory and recurrent vitiligo are heterogeneous and partially overlapping clinical issues rather than a single biological damage requiring a uniform management strategy. Oxidative stress serves as a critical factor in the pathogenesis of vitiligo, linking melanocyte injury, release of danger-associated molecular patterns (DAMPs), innate immune activation, and IFN-γ driven adaptive immune amplification, associated with active and refractory disease. Interleukin (IL)-15-dependent tissue-resident memory T (TRM) cells provide a mechanism for local immune reactivation and recurrence. However, the role of oxidative stress in treatment resistance and recurrence remains incompletely defined. Importantly, available studies of antioxidant therapy are heterogeneous, with no evidence demonstrates that antioxidant therapy eliminates TRM cells or prevents recurrence. In this review, we propose a hypothesis-generating clinical framework that distinguishes refractory and recurrent vitiligo based on disease activity, IFN-γ signaling, anatomical sites, phototherapy responses and recurrence risk. Currently, antioxidant therapy should be considered as an investigational adjunctive therapy. The review investigates the relationship between oxidative stress and antioxidant therapy in refractory and recurrent vitiligo, and evaluates the role of antioxidant therapy in the management of vitiligo. In the future, it will be essential to conduct prospective biomarker based stratified clinical trials to define the targeted vitiligo patients for antioxidant combination therapies, as well as to continuously develop novel antioxidant-based anti-inflammatory therapeutic approaches for refractory and recurrent vitiligo.

SOM3355 is a β1-blocker and a vesicular monoamine transporter type 1 and 2 inhibitor developed for the treatment of Huntington's disease (HD). Its novel polypharmacology makes it suited for the effective and safe treatment of chorea and other HD symptoms.

Aliovalent A- and B-site co-doping of the Ruddlesden-Popper layered perovskite La2NiO4 is demonstrated as a rational strategy to tune redox properties and enhance catalytic performance in dry reforming of methane. Sr[2+] substitution at the A-site of La1.6Sr0.4Ni1-y Cu y O4 induces Ni[2+] → Ni[3+] oxidation and changes in the oxygen-deficient surface environment, enhancing surface basicity and CO2 chemisorption. Progressive Cu[2+] incorporation at the B-site lowers the thermodynamic threshold for Ni reduction forming bimetallic NiCu alloy phases at substantially lower temperatures than the pure Ni exsolution. Among the catalysts, La1.6Sr0.4Ni0.7Cu0.3O4 exhibited superior performance with negligible coke deposition. In situ FTIR analysis, together with XPS results, suggested the formation of carbonate, CH x , CH x O, formate, and COOH surface intermediates, indicating the involvement of diverse surface species during DRM that may involve reactive surface oxygen species. This work establishes synergistic Sr/Cu co-doping of La2NiO4 as an effective, scalable approach for active, selective, and coke-resistant catalysts for syngas production via dry reforming of methane.