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A cellulose nanocrystal (CNC)-annealed hydrogel (CAH) structure, including doxorubicin (DOX) and 2-deoxy-d-glucose (2DG), was developed for local chemo-metabolic therapy (LCMT) of melanoma. DOX has been used as a chemotherapeutic agent because of its intercalation into DNA and generation of free radicals. 2DG has been used as a glycolytic inhibitor in multiple metabolic therapies in combination with DOX. Covalent and non-covalent (i.e., ionic and hydrogen bonding) binding approaches between CNC and drug cargo (i.e., DOX and 2DG) were used to tune the rheological properties of the CAH structure to achieve sustained drug release. Reduction of reduced nicotinamide adenine dinucleotide phosphate, adenosine triphosphate, and mitochondrial membrane potential, and elevation of cellular reactive oxygen species and cleaved caspases 3 and 7 were observed following treatment with CNC/DOX/2DG in B16F10 cells. Glutathione depletion, enhanced lipid peroxidation, and decreased lactate levels were observed in the CNC/DOX/2DG group. After intratumoral injection of the CNC/DOX/2DG hydrogel into B16F10 tumor-bearing mice, stronger tumor growth suppression and anti-recurrence capabilities were observed. These findings imply that the viscoelastically modulated CAH system can be a strong candidate for LCMT of melanoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Here, we present a protocol for isolating microvessels from fresh or snap-frozen brain tissue from mice and humans, followed by visualization of RNA utilizing RNAscope hybridization for quantification of mRNA. We describe the steps for sample preparation and isolation, fixation, and hybridization. This protocol was specifically designed to integrate with RNAscope in situ hybridization. Although the protocol was developed in a mouse model, it can be optimized for use in other organisms, including human brain samples., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study explored the vasodilatory mechanisms of the sodium-glucose cotransporter-2 inhibitor remogliflozin using femoral arteries of rabbits. Remogliflozin dilated femoral arterial rings pre-contracted with phenylephrine in a concentration-dependent manner. Pretreatment with the Ca 2+ -sensitive K + channel inhibitor (paxilline), the ATP-sensitive K + channel inhibitor (glibenclamide), or the inwardly rectifying K + channel inhibitor (Ba 2+ ) did not alter the vasodilatory effect. However, vasodilation was significantly reduced by pretreatment with the voltage-dependent K + (Kv) channel inhibitor (4-AP) and with the Kv1.5 subtype inhibitor (DPO-1) but not with Kv2.1 or Kv7 subtype inhibitor. Neither endothelium removal nor the inhibition of nitric oxide production altered the vasodilatory effect of remogliflozin. However, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid effectively reduced the remogliflozin effect, as did pretreatment with cGMP/PKG-related but not cAMP/PKA-related signaling pathway inhibitors. These results indicate that remogliflozin-mediated dilation of the femoral artery occurs via the activation of Kv channels, mainly the Kv1.5 subtype, SERCA pump, and cGMP/PKG-related signaling pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Perpendicular nanochannel creation of two-dimensional (2D) nanostructures requires highly controlled anisotropic drilling processes of the entire structure via void formation. However, chemical approaches for the creation of porosity and defects of 2D nanostructures have been challenging due to the strong basal plane chemical stability and the use of harsh reactants, tending to give randomly corroded 2D structures. In this study, we introduce Lewis acid-base conjugates (LABCs) as molecular drillers with attenuated chemical reactivity which results in the well-defined perpendicular nanochannel formation of 2D TiS 2 nanoplates. With the treatment of LABCs, tris(trimethylsilyl)pnictogens (TMS 3 P or TMS 3 As), high resolution perforation of TiS 2 nanoplates was achieved while maintaining their initial shape and structures. Such perforated TiS 2 nanoplates are tunable in their channel diameter between 4 and 10 nm with 2 nm resolution. With their increased surface area and enhanced adsorption of Li 2 S x , perforated TiS 2 nanoplates served as a diffusion barrier of lithium-sulfur (Li-S) cells, leading to a 2.5-fold improvement in cell performance compared to pristine TiS 2 nanoplates. Our molecular design concept for attenuated reactivity of LABCs is simple and could serve as a new approach for chemical drilling processes of 2D metal chalcogenides.

Polydimethylsiloxane (PDMS) is extensively employed in applications ranging from flexible electronics to microfluidics due to its elasticity, transparency, and biocompatibility. However, enhancing interfacial adhesion and tensile properties remains a challenge for applications demanding high mechanical stability. To this end, this study introduced a novel bonding technique using crosslinkers as adhesive layers to improve the mechanical performance of PDMS. By adjusting the crosslink density at the PDMS-PDMS interfaces, we achieved substantial improvements in tensile properties and interfacial adhesion. Our findings revealed that, under specific conditions, a particular mixing ratio significantly enhances the elastic modulus and interfacial stability. Notably, the elastic modulus of PDMS with a tailored crosslink density increased by approximately 760% compared to that achieved with a simple bonding method. This study demonstrated an effective strategy for tailoring the interfacial properties of PDMS by adjusting the crosslink density, offering a pathway to enhance material design for applications requiring advanced mechanical performance and stability.

In response to the growing demand for healthier food, online fresh food platforms have emerged as a convenient solution, aiming to meet this need. This study employs a difference-in-differences design and an imputation method to evaluate the impact of online fresh food platforms on population health. These methodological approaches enable the identification of causal effects, offering insights into how these platforms influence health outcomes across different demographic groups. Our findings reveal that the availability of online fresh food options positively influences health outcomes by increasing physical activity, such as walking time, and reducing BMI, hypertension, and depression rates. Easier access to healthier food fosters healthier lifestyles, contributing to both improved physical and mental health. These findings may offer insights for policymakers, suggesting that the availability of accessible healthy diet options could contribute to improving community health., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immunotherapy, particularly immune checkpoint blockade (ICB) therapies, has revolutionized oncology. However, it encounters challenges such as inadequate drug accumulation and limited efficacy against "cold" tumors characterized by lack of T cell infiltration and immunosuppressive microenvironments. Here, a controlled antibody production and releasing nanoparticle (CAPRN) is introduced, designed to augment ICB efficacy by facilitating tumor-targeted antibody production and inducing photodynamic cell death. CAPRN achieves tumor-specific accumulation via pH-responsive PEG detachment, enabling efficient intracellular gene delivery encoding anti-PD-L1 antibody. Laser-induced photodynamic therapy (PDT) not only triggers cancer cell death but also facilitates targeted antibody release from dying tumor cells. CAPRN demonstrates significant anti-tumor efficacy, attributed to multiple effects including enhanced antibody release, dendritic cell (DC) maturation, and T cell activation. Moreover, CAPRN exhibits substantial tumor suppression in both primary and bilateral tumor models, accompanied by activated T cell infiltration and enhanced immune responses. This study presents a novel strategy for priming robust immunotherapy, offering targeted antibody release through laser-assisted photodynamic nanoparticles., (© 2025 Wiley‐VCH GmbH.)

Trait mindfulness refers to one's disposition or tendency to pay attention to their experiences in the present moment, in a non-judgmental and accepting way. Trait mindfulness has been robustly associated with positive mental health outcomes, but its neural underpinnings are poorly understood. Prior resting-state fMRI studies have associated trait mindfulness with within- and between-network connectivity of the default-mode (DMN), fronto-parietal (FPN), and salience networks. However, it is unclear how generalizable the findings are, how they relate to different components of trait mindfulness, and how other networks and brain areas may be involved. To address these gaps, we conducted the largest resting-state fMRI study of trait mindfulness to-date, consisting of a pre-registered connectome-based predictive modeling analysis in 367 meditation-naïve adults across three samples collected at different sites. In the model-training dataset, we did not find connections that predicted overall trait mindfulness, but we identified neural models of two mindfulness subscales, Acting with Awareness and Non-judging. Models included both positive networks (sets of pairwise connections that positively predicted mindfulness with increasing connectivity) and negative networks, which showed the inverse relationship. The Acting with Awareness and Non-judging positive network models showed distinct network representations involving FPN and DMN, respectively. The negative network models, which overlapped significantly across subscales, involved connections across the whole brain with prominent involvement of somatomotor, visual and DMN networks. Only the negative networks generalized to predict subscale scores out-of-sample, and not across both test datasets. Predictions from both models were also negatively correlated with predictions from a well-established mind-wandering connectome model. We present preliminary neural evidence for a generalizable connectivity models of trait mindfulness based on specific affective and cognitive facets. However, the incomplete generalization of the models across all sites and scanners, limited stability of the models, as well as the substantial overlap between the models, underscores the difficulty of finding robust brain markers of mindfulness facets., (© 2025 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Radiotherapy is a widely employed technique for eradication of tumor using high-energy beams, and has been applied to approximately 50% of all solid tumor patients. However, its non-specific, cell-killing property leads to inevitable damage to surrounding normal tissues. Recent findings suggest that radiotherapy-induced tissue damage contributes to the formation of a pro-tumorigenic microenvironment. Methods: Here, we utilized two mouse strains and two organ-targeted radiotherapy models to uncover the mechanisms underlying the development of the radiotherapy-induced microenvironment. Results: Radiotherapy-induced tissue damage stimulates infiltration of monocyte-derived macrophages and their differentiation into M2 macrophages, ultimately leading to fibrosis and the formation of a pro-tumorigenic microenvironment. Notably, SRC family kinases (SFKs) emerged as crucial factors in the formation of the radiotherapy-induced pro-tumorigenic microenvironment. SFKs activation in epithelial cells and fibroblasts was triggered by direct exposure to irradiation or M2 macrophage cytokines. Remarkably, the administration of SFK-targeted inhibitors reversed myofibroblast activation, effectively ameliorating fibrosis and the pro-tumorigenic microenvironment in radiated tissues. Further, combined administration of radiotherapy and SFK-targeted inhibitors significantly enhanced the survival of tumor-bearing mice. Conclusions: Reshaping the tissue microenvironment by targeting SFKs is a potential strategy for preventing metastasis and recurrence following radiotherapy. The finding that clinically imperceptible damage can trigger a pro-tumorigenic microenvironment suggests the need for combining SFK-targeted inhibitors with radiotherapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Cathepsin D (Ctsd) has emerged as a promising therapeutic target for Alzheimer's disease (AD) due to its role in degrading intracellular amyloid beta (Aβ). Enhancing Ctsd activity could reduce Aβ42 accumulation and restore the Aβ42/40 ratio, offering a potential AD treatment strategy. Methods: This study explored Ctsd demethylation in AD mouse models using dCas9-Tet1-mediated epigenome editing. We identified dCas9-Tet1 as an effective tool for demethylating the endogenous Ctsd gene in primary neurons and in vivo brains. Results: Treatment with Ctsd-targeted dCas9-Tet1 in primary neurons overexpressing mutant APP (mutAPP) reduced Aβ peptide levels and the Aβ42/40 ratio. Additionally, in vivo demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Aβ levels and alleviated cognitive and behavioral deficits. Conclusion: These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Tinnitus, defined as the conscious awareness of a noise without any identifiable corresponding external acoustic source, can be modulated by various factors. Among these factors, tinnitus patients commonly report drastic increases of tinnitus loudness following nap sleep. Previous studies have suggested that this clinical pattern could be attributed to a somatosensory modulation of tinnitus. To our knowledge, no polysomnographic study has been carried out to assess this hypothesis., Methods: For this observational prospective study, 37 participants reporting frequent increases of tinnitus following naps were recruited. They participated to six full-polysomnography nap attempts over two days. Audiological and kinesiologic tests were conducted before and after each nap attempt., Results: 197 naps were collected. Each nap at each time of day elicited an overall significant increase in tinnitus minimum masking level (MML). Each inter nap period elicited an overall significant decrease. Tinnitus modulations were found significantly correlated with nap sleep duration (Visual numeric scale on tinnitus loudness, VNS-L, p < 0.05), with snoring duration (MML, p < 0.001), with snoring average sound level (VNS on tinnitus intrusiveness, VNS-I, p < 0.05) and with sleep apnea count (VNS-I, p < 0.001)., Conclusions: This study confirms objectively that tinnitus may increase following naps. No association was found between these modulations and somatosensory modulations involving the temporomandibular joint and cervical areas. However, it may be possible that nap-induced tinnitus modulations are a hidden form of somatosensory modulation as snoring and sleep apnea events are often related to tensor veli palatini muscle dysfunction., Competing Interests: Declaration of competing interest Damien Léger declares that in the past 5 years he has been employed as an investigator or a con-sultant by Actellion-Idorsia, the Agence Spatiale Européenne, Bioprojet, iSommeil, ESAI, Jan-senn, Jazz, Vanda, Merck, Philips, Rythm, Sanofi, Vitalaire, and Resmed. Robin Guillard declares that he is shareholder and president in Siopi SAS, and has a professional activity as independent as Robin Guillard EIRL. The other authors did not declare financial interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Salinity poses a significant challenge to plant growth and crop productivity by adversely affecting crucial processes, including photosynthesis. Efforts to enhance abiotic stress tolerance in crops have been hindered by the trade-off effect, where increased stress resistance is accompanied by growth reduction. In this study, we identified and characterized a plastocyanin gene (PaPC) from the Antarctic moss Polytrichastrum alpinum, which enhanced photosynthesis and salt stress tolerance in Arabidopsis thaliana without compromising growth. While there were no differences in growth and salt tolerance between the wild type and Arabidopsis plastocyanin genes (AtPC1 and AtPC2)-overexpressing plants, PaPC-overexpressing plants demonstrated superior photosynthetic efficiency, increased biomass, and enhanced salt tolerance. Similarly, PaPC-overexpressing rice plants exhibited improved yield potential and photosynthetic efficiency under both normal and salt stress conditions. Key amino acid residues in PaPC responsible for this enhanced functionality were identified, and their substitution into AtPC2 conferred improved photosynthetic performance and stress tolerance in Arabidopsis, tobacco, and tomato. These findings not only highlight the potential of extremophiles as valuable genetic resources but also suggest a photosynthesis-based strategy for developing stress-resilient crops without a growth penalty., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Cancer-derived small extracellular vesicles (sEVs) in body fluids hold promise as biomarkers for cancer diagnosis. For sEV-based liquid biopsy, isolation of sEVs with a high-purity and cancer-sEV detection with an extremely high sensitivity are essential because body fluids include much higher density of normal-cell-derived sEVs and other biomolecules and bioparticles. Here, we propose an isolation-analysis-integrated cancer-diagnosis platform based on dielectrophoresis(DEP)-ELISA technique which enables a three orders of magnitude higher sensitivity over conventional ELISA method and direct cancer diagnosis from blood plasma with high accuracy. The limit of detection (LOD) for sEVs in human plasma was as low as 10 4 sEVs/mL without a time-consuming and low-yield sEV isolation and purification process. The capability of this platform was validated by monitoring mice with cancer cell inoculation and assessing the effect of cancer-sEV-inhibiting drug. Using the developed sEV-based liquid biopsy, we diagnosed clinical samples from healthy donors (N = 39) and cancer patients (N = 90). The diagnostic accuracy was 94.2%, 98.6%, and 91.3% for breast, colon, and lung cancers, respectively. This integrated sEV isolation and analysis platform could be applied for high-sensitivity biomarker profiling and sEV-based liquid biopsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the effectiveness of anterior subtenon triamcinolone (AST) injections in the management of refractory macular edema., Methods: This is a retrospective case series of consecutive eyes with refractory macular edema treated with AST at a single vitreoretinal surgeon's practice at Toronto Western Hospital, University of Toronto, Canada in 2018 to 2023. Refractory was defined as persistent macular edema with a central subfield thickness of 250 µ m or greater over a 24-week period, receiving at least four intravitreal antivascular endothelial growth factor injections. Vision outcomes and optical coherence tomography features for all eyes were compared for three visits pre-AST treatment and two visits post-AST treatment., Results: Ninety-three patients (119 eyes); diabetic macular edema (26%), and pseudophakic cystoid macular edema (74%), with a mean follow-up duration of 161 days were included. The presence of subretinal fluid ( P = 0.0013), central subfield macular thickness ( P < 0.0001), cube average thickness ( P = 0.0024), and macular cube volume ( P = 0.0017) significantly improved from pre-AST to post-AST treatment. Visual acuity also significantly improved from pre-AST treatment to post-AST treatment ( P < 0.0001). There was no significant change in the intraocular pressures from pre-AST to post-AST ( P = 0.7920), and no complications were noted throughout the follow-up period., Conclusion: The findings from this study suggest that AST injections show modest improvement in anatomical and functional outcomes and are safe for the treatment and management of refractory macular edema.

Vancomycin, a vital antibiotic for treating gram-positive bacterial infections, requires therapeutic drug monitoring (TDM) because of its substantial pharmacokinetic variability. While traditional TDM relies on steady-state trough concentrations, recent guidelines advocate the area under the concentration-time curve (AUC) as the target index. However, detailed protocols for AUC estimation are lacking, leading to potential discrepancies among institutions. We surveyed medical institutions in Korea regarding vancomycin TDM, including AUC estimation. Nineteen participants responded to the TDM case challenge under three patient scenarios. For an ordinary patient in Case 1, the overall CV for AUC values was 0.4% when both trough and peak concentrations were included in the AUC calculation and 1.9% when utilizing only the trough concentration. For Case 2, an older patient with obesity, the corresponding CV was 6.6%. For Case 3 with multiple trough concentrations, the CV was 15.6%, reflecting variations in the selective use of data. Although the agreements in Case 1 were good, significant variability in AUC estimation was noted in cases involving atypical patient characteristics or old TDM data. Our study provides insight into the current status of vancomycin TDM in Korea and underscores the need for standardized operational protocols for AUC estimation.