N-cadherin mechanosensing in ovarian follicles controls oocyte maturation and ovulation.

The cell adhesion molecule N-cadherin (CDH2) is a membrane component of adherens junctions which regulates tissue morphogenesis and architecture. In the follicles of mammalian ovaries, N-cadherin adherens junctions are present between granulosa cells, cumulus cells, and at the interface of cumulus cell transzonal projections and the oocyte. We demonstrate a mechanosensory role of N-cadherin integrating tissue structure and hormonal regulation of follicular morphogenic events including expansion of the cumulus-oocyte complex (COC) matrix, oocyte maturation, and ovulation.

Titania Nanopores as Photoelectrocatalysts for Coupling Hydrogen Production with Plastic Reformation.

Photoelectrochemical (PEC) water splitting offers a sustainable pathway for solar-to-chemical energy conversion, yet its efficiency is often limited by sluggish water oxidation and the generation of low-value oxygen. Here, the use of engineered titania nanopore (TNP) films is reported, fabricated via anodization and thermal annealing, as co-catalyst-free photoanodes for coupling hydrogen evolution reaction (HER) with polyethylene terephthalate (PET) reformation into high-value formate. By tuning the crystallographic phase of TiO from amorphous to anatase and rutile, the optimized anatase-phase electrode exhibits excellent PEC performance in a two-electrode configuration, achieving a high steady-state photocurrent density of [2.

Machine-Learning Approach to Increase the Potency and Overcome the Hemolytic Toxicity of Gramicidin S.

Antibiotic resistance is a global health crisis, with multidrug-resistant pathogens like methicillin-resistant (MRSA) demanding next-generation therapeutics. Tackling this silent pandemic requires innovative strategies beyond traditional drug discovery. We present a machine-learning (ML)-driven computational pipeline for redesigning FDA-approved drugs, applied here to the cyclic antibiotic gramicidin S, historically limited to topical use due to hemolytic toxicity.

Targeted activation of Nrf2 at sites of oxidative stress reverses doxorubicin-induced cognitive impairments in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, and processing speed, known as chemotherapy-induced cognitive impairment or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition.

Pb in targeted radionuclide therapy: a review.

Background: The selective delivery of α-emitting radionuclides is emerging as a highly effective form of cancer therapy. With a short range and high cytotoxicity, α-particles can selectively kill cancerous cells whilst minimising harm to surrounding healthy tissue. As the parent of the α-emitter Bi, Pb has seen increasing therapeutic use on account of its favourable chemistry, half-life, and decay properties.

Nanoporous anodic alumina-based gas sensors: insights into advances and perspectives.

Achieving high-performance gas sensing requires materials and transduction mechanisms that enhance sensitivity, selectivity, and stability, while addressing challenges such as cross-sensitivity and real-time operation. Conventional sensor platforms often involve trade-offs between response time, detection limits, and environmental robustness. Nanoporous anodic alumina (NAA) fabricated by electrochemical oxidation-anodization-of aluminum provides a tunable platform for engineering gas sensors with tailored structural and physicochemical properties, enabling diverse transduction mechanisms and sensor configurations.

Broad-Spectrum Gramicidin S Derivatives with Potent Activity Against Multidrug-Resistant Gram-Negative ESKAPE Pathogens.

Background/objectives: Multidrug-resistant Gram-negative ESKAPE pathogens, including , , , and , pose a significant global health threat. Gramicidin S, a potent cyclic antimicrobial peptide, is largely ineffective against these bacteria, and its high haemolytic toxicity limits its clinical usage. This study reports on several novel gramicidin S analogues with improved efficacy and safety profiles against multidrug-resistant Gram-negative bacteria.

Expanding the therapeutic window of gramicidin S towards a safe and effective systemic treatment of methicillin-resistant S. aureus infections.

The rise of multidrug-resistant bacteria, such as Methicillin-resistant Staphylococcus aureus (MRSA), necessitates the development of new antibacterial therapies. Antimicrobial peptides offer a promising alternative to conventional antibiotics due to their unique mechanisms of action. Gramicidin S exhibits potent bactericidal activity against S.

Site-specific drug release of monomethyl fumarate to treat oxidative stress disorders.

Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer-Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress.

New Potent Sulfonamide-Based Inhibitors of . Biotin Protein Ligase.

The key regulatory metabolic enzyme, biotin protein ligase (BPL), is an attractive target for the development of novel antibiotics against multi-drug-resistant bacteria, such as . Here we report the synthesis and assay of a new series of inhibitors (-) against . BPL (BPL), where a component sulfonamide linker was used to mimic the acyl-phosphate group of the natural intermediate biotinyl-5'-AMP ().

Elucidating Synergies of Single-Atom Catalysts in a Model Thin Film Photoelectrocatalyst to Maximize Hydrogen Evolution Reaction.

Realization of the full potential of single-atom photoelectrocatalysts in sustainable energy generation requires careful consideration of the design of the host material. Here, a comprehensive methodology for the rational design of photoelectrocatalysts using anodic titanium dioxide (TiO) nanofilm as a model platform is presented. The properties of these nanofilms are precisely engineered to elucidate synergies across structural, chemical, optoelectronic, and electrochemical properties to maximize the efficiency of the hydrogen evolution reaction (HER).

18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate.

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments.

Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function.

A New Gramicidin S Analogue with Potent Antibacterial Activity and Negligible Hemolytic Toxicity.

Antibiotic resistance is an urgent threat to global health, with the decreasing efficacy of conventional drugs underscoring the urgency for innovative therapeutic strategies. Antimicrobial peptides present as promising alternatives to conventional antibiotics. Gramicidin S is one such naturally occurring antimicrobial peptide that is effective against , with a minimum inhibitory concentration (MIC) of 4 μg/mL (3.

Detection of Volatile Organic Compounds through Spectroscopic Signatures in Nanoporous Fabry-Pérot Optical Microcavities.

Increasingly complex modern gas-monitoring scenarios necessitate advanced sensing capabilities to detect and identify a diverse range of gases under varying conditions. There is a rising demand for individual sensors with multiple responses capable of recognizing gases, identifying components in mixtures, and providing stable responses. Inspired by gas sensors employing multivariable response principles, we develop a nanoporous anodic alumina high-order microcavity (NAA-HOμCV) gas sensor with multiple optical outputs for discriminative gas detection.

Engineering of Solid-State Nanoporous Laser through Dendrimer-Encapsulated Fluorophores.

Dendrimers─nanosized macromolecules that can function as hosts for encapsulation of guest molecules─provide new avenues to engineer gain media for lasing systems. In this context, this study investigates the interplay between the geometric features of a model porous scattering medium, nanoporous anodic alumina (NAA), and the chemical features of a model fluorophore-dendrimer encapsulation system to maximize random lasing. The inner surface of the NAA platforms is functionalized with fluorophore molecules encapsulated within dendrimers via an electrostatic interaction.

Towards a High-Affinity Peptidomimetic Targeting Proliferating Cell Nuclear Antigen from .

Invasive fungal infections (IFIs) are prevalent in immunocompromised patients. Due to alarming levels of increasing resistance in clinical settings, new drugs targeting the major fungal pathogen are required. Attractive drug targets are those involved in essential processes like DNA replication, such as proliferating cell nuclear antigens (PCNAs).

Structure-guided design and synthesis of ATP-competitive N-acyl-substituted sulfamide d-alanine-d-alanine ligase inhibitors.

d-Alanine-d-alanine ligase (Ddl) catalyses the ATP-dependent formation of d-Ala-d-Ala, a critical component in bacterial cell wall biosynthesis and is a validated target for new antimicrobial agents. Here, we describe the structure-guided design, synthesis, and evaluation of ATP-competitive N-acyl-substituted sulfamides 27-36, 42, 46, 47 as inhibitors of Staphylococcus aureus Ddl (SaDdl). A crystal structure of SaDdl complexed with ATP and d-Ala-d-Ala (PDB: 7U9K) identified ATP-mimetic 8 as an initial scaffold for further inhibitor design.

Understanding the Intrinsic Rectification Properties of Nanoporous Anodic Alumina by Selective Chemical Etching.

The distribution of oxygen and aluminum vacancies across the hemispherical barrier oxide layer (BOL) of nanoporous anodic alumina (NAA) relies intrinsically on the electric field-driven flow of electrolytic species and the incorporation of electrolyte impurities during the growth of anodic oxide through anodization. This phenomenon provides new opportunities to engineer BOL's inherited ionic current rectification (ICR) fingerprints. NAA's characteristic ICR signals are associated with the space charge density gradient across BOL and electric field-induced ion migration through hopping from vacancy to vacancy.

Fortuitous Compound Degradation Produces a Tractable Hit against Dethiobiotin Synthetase: A Cautionary Tale of What Goes In Does Not Always Come Out.

We previously reported potent ligands and inhibitors of dethiobiotin synthetase (DTBS), a promising target for antituberculosis drug development (Schumann et al., . 2021, , 2339-2347); here, the unconventional origin of the fragment compound they were derived from is described for the first time.

Exploring Photoswitchable Binding Interactions with Small-Molecule- and Peptide-Based Inhibitors of Trypsin.

The ability to photochemically activate a drug, both when and where needed, requires optimisation of the difference in biological activity between each isomeric state. As a step to this goal, we report small-molecule- and peptide-based inhibitors of the same protease-trypsin-to better understand how photoswitchable drugs interact with their biological target. The best peptidic inhibitor displayed a more than fivefold difference in inhibitory activity between isomeric states, whereas the best small-molecule inhibitor only showed a 3.

Designing Fluorescent Nuclear Permeable Peptidomimetics to Target Proliferating Cell Nuclear Antigen.

Human proliferating cell nuclear antigen (PCNA) is a critical mediator of DNA replication and repair, acting as a docking platform for replication proteins. Disrupting these interactions with a peptidomimetic agent presents as a promising avenue to limit proliferation of cancerous cells. Here, a p21-derived peptide was employed as a starting scaffold to design a modular peptidomimetic that interacts with PCNA and is cellular and nuclear permeable.

Smart Wearable Patches Using Light-Controlled Activation and Delivery of Photoswitchable Antimicrobial Peptides.

A novel strategy to treat Staphylococcus aureus (S. aureus) skin infections is presented, where UV light is used to facilitate concomitant light-controlled activation and delivery of an antimicrobial therapeutic agent. Specifically, a new photoswitchable gramicidin S analogue was immobilized onto a polymeric wearable patch via a photocleavable linker that undergoes photolysis at the same wavelength of light required for activation of the peptide.

Uncovering the link between the restriction modification system and LuxS in meningitis isolates.

is capable of randomly switching their genomic DNA methylation pattern between six distinct bacterial subpopulations (A-F) via recombination of a type 1 restriction-modification locus, . These pneumococcal subpopulations exhibit phenotypic changes which favor carriage or invasive disease. In particular, the allele has been associated with increased nasopharyngeal carriage and the downregulation of the gene.