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Chronic stress is a major risk factor for anxiety disorders and is often accompanied by disruptions in female reproductive cyclicity, but the stress-responsive neural populations that shape these comorbid behavioral and physiological outcomes remain poorly defined. The bed nucleus of the stria terminalis (BNST) is a major node for sustained anxiety and stress integration, yet the contribution of genetically defined BNST neurons to restraint stress is not fully resolved in females. Here, we identify proenkephalin-expressing neurons in the anterior dorsal BNST (adBNSTPENK) as a restraint-responsive population that constrains anxiety-like behaviors and modulates cytology-based estrous cycle organization. Acute chemogenetic inhibition of adBNSTPENK neurons produced anxiety-like behaviors in females, whereas activation attenuated acute restraint stress (ARS)-induced anxiety-like behaviors. Female mice subjected to chronic restraint stress (CRS) exhibited both anxiety-like avoidance and disrupted estrous-cycle organization, which can be mitigated by sustained activation of adBNSTPENK neurons. These findings suggest that adBNSTPENK neurons form a stress-recruited limbic circuit node that buffers stress-induced anxiety-like behaviors and is associated with improved vaginal cytology-based estrous-cycle organization under chronic stress.

Achieving programmable photoisomerization of azobenzenes in the solid-state remains a long-standing challenge for photoresponsive materials. Here, we introduce a dynamic soft-confinement strategy using bubble-assisted assembly to manipulate molecular aggregation via tunable surface energy at the solid-liquid interface. By controlling the morphologies of microfluidic channels (necktie-like, strip-like, and necklace-like), we achieve distinct self-assembled aggregates of microcubes, corded scaffolds, and microplates, with tailored freedom of the photoswitchable molecule. The strip-like channel, formed by thinning bubble walls, traps metastable intermediates, yielding a corded scaffold structure with favorable light penetration, weaker intermolecular interactions, and loosened molecular packing for isomerization. This design achieves near-quantitative bidirectional E⇆Z photoisomerization (96%-98%) in the solid-state, rivaling solution-like performance. Multi-scale characterization and computational analyses reveal the critical role of confined aggregation kinetics in controlling molecular motion. Furthermore, heterogeneous patterning demonstrates programmable photoresponsive arrays for photomechanical applications. This strategy provides a scalable platform for dynamically controlling supramolecular self-assembly pathways and designing solid-state photoresponsive materials with programmable functions.

Artificial intelligence (AI) models can create radiological images. We aimed to determine whether radiologists could distinguish AI-generated from real images, and factors associated with correct classification. AI-generated images were made using an implementation of the Dreambooth fine-tuning approach applied to Stable Diffusion v2.1. Radiologists were asked to classify images as real (n = 10) or AI-generated (n = 20) and their confidence in this decision (1 least, 5 most) in an online form. 182 radiologists completed the survey. The median proportion of correctly identified images per respondent was 77.8% (interquartile range, IQR 70.0, 86.7%), with no difference between AI-generated (75.0%, IQR 70.5, 87.1%) and real images (83.4%, IQR 74.2, 92.6%, p = 0.19). Ultrasound and X-ray were more likely to be correctly identified than cross-sectional images like CT or MRI (88%, 91%, 70% and 77% respectively, p = 0.015). Mean confidence was similar for AI-generated and real images (3.50 ± 0.23 versus 3.56 ± 0.23, p = 0.49). There was no difference in classification based on number of years of experience (p = 0.57) or familiarity with AI (p = 0.37). However, radiologists with relevant specialist interests were more likely to correctly classify images (80.7 ± 1.3% versus 76.9 ± 0.8%, p = 0.012). Radiologists were only able to correctly identify three-quarters of AI-generated images. This was impacted by sub-specialist expertise but not the number of years of experience or familiarity with AI.

Patient-derived organoids (PDOs) are widely used preclinical models for colorectal cancer (CRC). However, conventional PDO cultures frequently lose tumor microenvironment (TME) components and undergo culture-induced transcriptional drift. A chemically defined induction system (CiPDO) has been proposed to preserve fetal-like plasticity states, yet a direct single-cell comparison of CiPDO versus conventional PDO against the matched primary tumor is lacking. To evaluate and compare the single-cell transcriptional fidelity of chemically induced PDO (CiPDO) and conventional PDO (current_PDO) relative to the matched primary colorectal tumor, using a publicly available scRNA-seq dataset. We re-analyzed the public scRNA-seq dataset GSE261012, which profiled cells from the primary tumor, conventional PDO (current_PDO), and chemically induced PDO (CiPDO) of the same CRC patient. Using Scanpy, we performed quality control, clustering, cell type annotation, and module scoring for oncofetal-like state (OnFS), proliferation, stress/hypoxia, epithelial-mesenchymal transition (EMT), and differentiation signatures. All possible pairwise comparisons among the three conditions were performed using two-sided Mann-Whitney U tests. For each module score, we provided biological interpretation of the score magnitude, reference ranges from established CRC single-cell atlases, and contextualization of the observed values. After quality control, 16,249&#x202f;cells were retained across 19 clusters. Both PDOs completely lost TME components (fibroblasts, myeloid, T cells) compared with the primary tumor. At the epithelial-cell level, CiPDO showed significantly higher OnFS scores than current_PDO (0.189 vs. 0.102, p&#x202f;<&#x202f;0.001) and both PDOs exhibited significantly higher OnFS than the primary tumor (-0.232; both p&#x202f;<&#x202f;0.001). Proliferation scores were highest in the primary tumor (1.461), intermediate in current_PDO (0.983), and lowest in CiPDO (-0.314); all pairwise differences were significant (p&#x202f;<&#x202f;0.001) except primary tumor vs. current_PDO (p = 0.082). Stress/hypoxia scores were significantly elevated in current_PDO (0.286) compared with both CiPDO (0.052, p&#x202f;<&#x202f;0.001) and the primary tumor (0.195, p = 0.041). Differentiation scores did not differ significantly between the two PDO conditions (p = 0.171), whereas both PDOs showed significantly higher differentiation than the primary tumor (both p&#x202f;<&#x202f;0.001). EMT scores showed a small but statistically significant difference between CiPDO (-0.078) and current_PDO (-0.098, p&#x202f;<&#x202f;0.001), and both were significantly higher than the primary tumor (-0.128; both p&#x202f;<&#x202f;0.001). Within the constraints of a single-patient design, CiPDO better preserves the oncofetal-like plasticity state of primary CRC epithelial cells while exhibiting fewer culture-induced proliferation and stress signatures than conventional PDO. Differentiation states were comparable between the two PDO conditions. These findings support the use of chemically defined induction to improve PDO fidelity for studying tumor cell plasticity, although validation in larger cohorts is required.

Symbiont-bearing benthic foraminifera, like corals, rely on endosymbionts for growth and nutrition and experience bleaching under heat stress. Sorites orbiculus, found in tropical and subtropical waters, hosts a diverse range of endosymbionts belonging to Symbiodiniaceae. We examined the thermal tolerance of the Red Sea population, which is the source of an established, invasive population of S. orbiculus in the Eastern Mediterranean. The Red Sea population is expected to exhibit enhanced thermotolerance, potentially due to its greater variety of endosymbionts. We conducted temperature-manipulation experiments, measuring calcification rates and net photosynthesis, evaluating the thermotolerance of S. orbiculus and its endosymbionts. We also analyzed the diversity of Symbiodiniaceae by sequencing the internal transcribed spacer 2 (ITS2). Our results show that exposure to 35&#xb0;C initially induced stress in the endosymbionts during the first week; however, net photosynthesis gradually recovered in subsequent weeks. In contrast, host calcification rates remained low at 35&#xb0;C, though not completely inhibited. Amplicon sequencing revealed that by the end of the experiment, a single ITS2 type, belonging to Symbiodiniaceae Clade F2 and initially present in field-collected specimens, became dominant in cultured individuals. Because this type became dominant across all temperature treatments, the observed shift likely reflects a response to laboratory conditions rather than direct thermal selection. Consequently, although the recovery at 35&#xb0;C is consistent with acclimatory physiological responses, it does not provide direct evidence for symbiont-specific acclimation. Our findings suggest that holobiont physiological recovery and symbiont shuffling under laboratory conditions may contribute to the resilience of S. orbiculus in warming oceans.

Deeper understanding of ketamine's mechanism of action would contribute to the discovery of novel therapeutic targets with fast-onset actions. To gain insight on the mechanism underlying the antidepressant-like effects of ketamine, we focused on perineuronal nets (PNNs), an extracellular matrix structure that surrounds fast-spiking parvalbumin-positive interneurons and regulates synaptic plasticity, whose integrity is known to be compromised under stress-induced depressive conditions. We first performed the description of the plastic remodeling of PNNs in the Chronic restraint stress (CRS) mice treated or un-treated with ketamine, by quantifying the number of WFA, marker of PNNs, parvalbumin (PV) and c-Fos positive cells, as a surrogate of neuronal activity. And then, we investigated the the transcripts of a number of proteins involved in the formation or degradation of PNNs with or without ketamine in CRS mice. Next, we evaluated the expression of IBA1, a microglial marker, in the hippocampus and medial prefrontal cortex after CRS treated or un-treated with ketamine. We found that ketamine effectively alleviated the animals' depression like behavior as well as attenuates CRS-induced reduction of WFA-positive cells in the hippocampus and medial prefrontal cortex of mice. Although ketamine treatment had little or no effect on the number of PV, c-Fos positive cells and the transcripts of proteins involved in the formation or degradation of PNNs. Notably, ketamine treatment lead to remarkably reduced the number of IBA1-positive cells in the hippocampus and medial prefrontal cortex after CRS. Our findings suggest that PNNs is characterized by region-specific changes in chronic stress mouse brain and provide extensive evidence that ketamine exposure initiates microglia to remodel PNN, instead of the PNN accumulation and degradation enzymes.

Diffuse large B-cell lymphoma (DLBCL) can be subclassified by phenotype into germinal center B-cell-like and activated B-cell-like (ABC) subtypes and by recurrent potentially oncogenic mutations into 5 to 7 genetic clusters. In ABC-DLBCL, potentially oncogenic mutations frequently occur in genes involved in B-cell receptor (BCR) signaling and NF-&#x3ba;B activation. Autonomous BCR signaling acts as an alternative immunologic driver predominantly in ABC-type DLBCL that cannot be captured by either subclassification system. The relative functional contribution and interdependence of these mechanistically diverse oncogenic drivers have not been completely defined. To directly compare the effects of autonomously signaling BCR and signalosome-activating CARD11 mutations on NF-&#x3ba;B activation and survival of ABC-DLBCL, we reciprocally exchanged these driver mechanisms in the MYD88L265P-mutated ABC-DLBCL cell lines TMD8 and OCI-Ly3. Only CARD11L251P (not CARD11K215N, CARD11D230N, and CARD11R337Q) compensated TMD8 cells for the loss of autonomous BCR signaling, as indicated by survival of BCR knockout and conversion to complete resistance to acalabrutinib. Transduction of the TMD8 BCR rescued OCI-Ly3 cells from replacing the CARD11L215P variant with CARD11WT. The autonomous TMD8 BCR signal provided a slight growth advantage over CARD11L251P-driven cells in both reciprocal systems. Unsupervised clustering of genetically engineered TMD8 and OCI-Ly3 clones demonstrated tight clustering with their parental cells and only minor alterations of cellular pathways. Only the strongest signalosome-activating mutation has functional near-equivalency to an autonomously signaling BCR for NF-&#x3ba;B activation and growth and survival in ABC-DLBCL. Quantifying the effects of co-occurring potential NF-&#x3ba;B-activating mechanisms is essential to predict Bruton tyrosine kinase (BTK) inhibition sensitivity in individual ABC-DLBCL cases.

Irreversible electroporation (IRE) utilizes high-voltage pulses to permeabilize cell membranes and induce cancer cell death, a process that releases damage-associated molecular patterns (DAMPs) and triggers immune responses. This study investigated the impact of intracellular DAMPs, extracted following cell treatment with electric pulses and termed electroporation supernatant (EP SN), on the viability of cancerous (4T1) and noncancerous (CHO) cells using an in vitro model. Viability was assessed via MTT, flow cytometry, and clonogenic assays. Protein, RNA, and DNA extraction levels were quantified using the BCA assay, SDS-PAGE, RT-PCR, and PCR, while cell integrity was confirmed through Cell Mask. Results revealed that EP SN rich in DAMPs enhanced cell resilience post-electroporation, with a more pronounced protective effect observed in 4T1 cells. We confirmed that DAMP release resulted from pulsing-induced permeabilization rather than cell lysis. Analysis showed that up to 65% of intracellular protein and significant amounts of RNA were released in a pulse-dependent manner, whereas DNA extraction remained negligible. Interestingly, heat-inactivation of the EP SN did not diminish its protective effect, suggesting that the improved viability is not dependent on the biochemical activity of the DAMPs. Instead, the data suggest that macromolecules like proteins and RNA stabilize cell homeostasis through colloidal osmotic pressure or Gibbs-Donnan effects. Consequently, the presence of these DAMPs during treatment may increase the resistance of cancerous 4T1 cells compared to noncancerous CHO cells, posing a potential challenge for IRE efficacy. To counteract this resistance, concomitant use of anticancer drugs like bleomycin or cisplatin is necessary.

This review provides an overview of current evidence on the presence, distribution, and physiological role of glucagon-like peptide-1 (GLP-1) receptors in skin tissue. Although GLP-1 receptor agonists are primarily used to treat type 2 diabetes mellitus and obesity, increasing evidence suggests that they may also have direct effects on the skin. This review examines the available research on GLP-1 receptor expression in major skin cell types, including keratinocytes, dermal fibroblasts, and the cutaneous microvascular endothelium. The strength of the evidence is evaluated according to the species studied, the experimental model used, and the method of receptor detection, including gene expression, protein identification, and functional activity. Differences in findings across animal models, cultured cells, and human tissue are also considered. In addition, this review distinguishes between skin effects that are likely mediated by direct activation of GLP-1 receptors within cutaneous tissue and those that occur indirectly through systemic metabolic improvement or modulation of immune and inflammatory pathways.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown clinical efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD), yet their therapeutic performance appears limited in several recurring settings, including advanced fibrosis, metabolically milder populations, and treatment discontinuation. These limitations suggest that treatment responses are shaped not only by pharmacological potency, but also by the regulatory systems through which GLP-1RAs act. Here, we propose a conceptual multi-layered framework in which GLP-1R-based therapies improve hepatic outcomes predominantly, although not exclusively, through indirect and systemic metabolic regulation. Within this framework, therapeutic responses may be influenced by the integrity of intrahepatic and systemic signaling networks, the magnitude of baseline metabolic perturbation, and the persistence of pharmacological input, which can be interpreted as structural, contextual, and temporal constraints. Multi-receptor agonists may partially mitigate these constraints by expanding regulatory inputs through glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon receptor (GCGR) co-activation. However, receptor-level modulation alone may remain insufficient to ensure durable responses after treatment withdrawal. We further discuss the gut microbiota and its metabolites as a candidate system-level regulatory layer that integrates host metabolic, immune, and endocrine signaling. Across diverse interventions, convergence appears more consistent at the level of microbiota-associated metabolic functions than taxonomic composition, but its causal significance remains incompletely established. Cross-intervention convergence analysis may therefore serve as a hypothesis-generating strategy to identify recurrent microbiota-metabolite axes with potential mechanistic and therapeutic relevance.

Paraneoplastic acral vascular syndrome is a rare condition associated with various malignancies, most commonly adenocarcinomas. It manifests as digital ischemia, including Raynaud's phenomenon, acrocyanosis, and digital gangrene. Reported cases typically show improvement after treatment of the underlying cancer. We describe the first known case of paraneoplastic acral vascular syndrome secondary to papillary thyroid carcinoma (PTC), with complete resolution following thyroidectomy. A 37-year-old previously healthy woman was referred from the vascular surgery clinic for evaluation of episodic digital discoloration. She reported a four-year history of recurrent Raynaud-like color changes affecting the middle fingers of both hands and the lateral four toes of both feet. She denied symptoms suggestive of connective tissue disease, inflammatory arthritis, autoimmune disorders, or cardiovascular disease, as well as tobacco or alcohol use. On examination, her feet were cold, with ulcers on the first and second toes of the right foot. Peripheral pulses in the lower extremities were diminished, with bilaterally weak dorsalis pedis pulses, more pronounced on the right.Her autoimmune panel was positive for anti-nuclear, anti-dsDNA, and anti-centromere antibodies. Capillaroscopy and arterial Doppler ultrasound of the lower limbs were unremarkable. Her symptoms progressed despite multiple treatments, leading to gangrene of the first and second toes of the right foot. A positron emission tomography (PET) scan showed no evidence of vasculitis but revealed focal uptake in a 1.14 cm nodule in the right thyroid lobe. Fine-needle aspiration suggested PTC. She underwent thyroidectomy, and histopathology confirmed papillary carcinoma along with medium-sized vessels showing intimal thickening and marked luminal narrowing, consistent with vasculitis. At 18month followup, she demonstrated complete clinical resolution with no new ulcerations. Paraneoplastic acral vascular syndrome is a rare condition that resembles Raynaud's phenomenon and may improve after treatment of the associated cancer. This case emphasizes the importance of considering occult cancer in patients with unexplained digital ischemia.

Insomnia is a prevalent sleep disorder associated with intestinal barrier dysfunction and immune dysregulation. Mongolian warm acupuncture (MWA) has shown therapeutic potential in insomnia; however, its effects on intestinal permeability and underlying mechanisms remain unclear. In this study, an insomnia rat model was established using chronic unpredictable mild stress combined with para-chlorophenylalanine (PCPA). To evaluate the therapeutic effects of MWA, comparative analysis was conducted among different groups, including Control, Model, MWA, Estazolam, and sham MWA groups. MWA group showed significantly improvement on sleep quality, cognitive performance, and anxiety-like behavior and alleviated colonic tissue damage. MWA treatment attenuated intestinal barrier dysfunction by modulating the expression of ZO-1, Occludin, and Claudin-4. In addition, MWA reduced inflammatory responses by decreasing TNF-&#x3b1;, IL-1&#x3b2;, and IL-6 levels while increasing IL-22 expression. Furthermore, MWA suppressed activation of the TLR4/MyD88/NF-&#x3ba;B signaling pathway. These findings suggest that MWA exerts protective effects against insomnia-associated intestinal barrier dysfunction and inflammation and may represent a promising non-pharmacological therapeutic strategy for insomnia.

A 69-year-old female was admitted with a four-day history of unexplained fever. Lung examination revealed coarse breath sounds, and laboratory tests showed elevated inflammatory markers. She had no identifiable environmental or occupational exposure, and initial screening for common respiratory pathogens was negative. Chest computed tomography (CT) scan demonstrated patchy ground-glass opacities and reticular shadows distributed along the bronchovascular bundles in the right upper lobe and dorsal segments of both lower lobes, with lesions showing the reversed halo sign (RHS). Initial empirical antibiotic therapy was ineffective. Subsequent bronchoalveolar lavage (BAL) culture yielded heavy growth of Pseudomonas putida, with negative fungal and tuberculosis nucleic acid testing. Based on antimicrobial susceptibility testing, the treatment regimen was adjusted to a combination of ceftazidime and amikacin. Following this targeted therapy, the patient's symptomatic improvement occurred while imaging abnormalities persisted, indicating a clinical-radiological dissociation. The patient was discharged after a 15-day hospital stay. This case highlights the following: (1) In community-acquired pneumonia with atypical imaging features (such as the RHS) that is refractory to conventional therapy, the differential diagnosis should be expanded to include environmental opportunistic pathogens like P. putida; (2) The RHS is a non-specific imaging finding, and its diagnostic significance must be interpreted in conjunction with lesion distribution, dynamic changes, and the complete clinical context; (3) Obtaining microbiological evidence through minimally invasive techniques such as BAL is crucial for shifting from empirical to precise targeted therapy, thereby improving patient prognosis.

Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes and obesity. Despite its clinical efficacy, oral administration remains challenging because of its limited gastrointestinal stability, poor epithelial permeability, and low affinity for lipid-based delivery systems. In the present study, a combined hydrophobic ion pairing (HIP) and solid lipid nanoparticle (SLN) approach was explored to improve semaglutide incorporation and delivery-related properties. Semaglutide was complexed with the cationic lipid DOTAP at different molar ratios (1:0-1:18) and subsequently incorporated into cetyl palmitate-based SLNs produced by microfluidic mixing using a herringbone device. The resulting formulations were characterized in terms of particle size, &#x3b6;-potential, encapsulation efficiency, morphology, solid-state organization, colloidal stability, release behavior, mucus interaction, cytocompatibility, and epithelial permeability. Among the various formulations prepared, the one prepared with a molar ratio semaglutide: DOTAP of 1:18 and a peptide concentration of 10% (w/w) (F10) showed the best results, combining particle sizes of less than 300&#x202f;nm with almost complete encapsulation efficiency and a highly positive &#x3b6;-potential. FTIR, DSC, TGA and SAXS analyses confirmed the correct formation of the complex and its incorporation into the lipid matrix. The F10 formulation demonstrated good stability under simulated gastrointestinal conditions and a sustained-release profile. The formulation also exhibited strong interactions with mucus, whilst retaining the ability to diffuse through the mucin network. Cytocompatibility studies demonstrated acceptable cell viability at relevant concentrations, whilst permeability experiments through Caco-2 monolayers revealed an approximately 6-fold increase in apparent permeability compared to free semaglutide. Therefore, these findings indicate that the combination of DOTAP-mediated hydrophobic ion pairing and microfluidic-assisted SLN production represents a potentially promising strategy for improving semaglutide encapsulation, gastrointestinal stability, and epithelial transport, while maintaining a favorable balance between mucus interaction and mucodiffusion.

Metal sulfide nanomaterials have emerged as promising photothermal agents for cancer therapy owing to their strong near-infrared absorption, favorable biocompatibility, and tunable surface chemistry. However, insufficient tumor accumulation and limited immunological activation remain major obstacles restricting their therapeutic efficacy in solid tumors. Herein, we report a macrophage-assisted delivery strategy based on hyaluronic acid-engineered copper sulfide nanoparticles (HA@CuS NPs) for enhanced photothermal-immunotherapy against osteosarcoma. In this system, adoptively transferred RAW264.7 macrophages were intravenously administered to increase macrophage enrichment within the osteosarcoma microenvironment, while HA@CuS NPs were rationally designed to target both tumor cells and tumor-associated macrophages through HA-mediated cellular recognition. The HA-coated CuS nanoparticles displayed good colloidal stability, efficient near-infrared photothermal conversion, and enhanced cellular uptake by osteosarcoma cells and macrophages. Importantly, macrophages acted as cellular reservoirs for CuS nanoparticles, promoting tumor accumulation and improving intratumoral photothermal distribution. Under 808-nm laser irradiation, the combined macrophage/HA@CuS treatment produced stronger tumor heating and more effective osteosarcoma ablation than HA@CuS nanoparticles alone. Beyond direct photothermal killing, HA@CuS nanoparticles also remodeled the tumor immune microenvironment by promoting M1-like polarization of tumor-associated macrophages, increasing IL-12p40 secretion, reducing IL-10 levels, and enhancing cytotoxic T lymphocyte infiltration. These immune-regulatory effects further amplified the antitumor response induced by photothermal therapy. Collectively, this study demonstrates that HA-engineered copper sulfide nanoparticles can function not only as metal sulfide photothermal agents but also as immunomodulatory nanomaterials. The integration of macrophage-assisted tumor delivery with CuS-based photothermal therapy provides a promising strategy for improving the therapeutic efficacy of metal-based nanomedicine against osteosarcoma.

In hinge epistemologies, epistemic justification for doxastic attitudes is possible only if a set of assumptions, called hinges, is taken for granted in our inquiries. While hinge epistemologists have focused on how hinges enable the justification of belief, they have not examined whether or how justified suspension of judgment fits within their framework. We argue that any attempt to account for justified suspension encounters two problems, both suggesting that suspension may depend on a hinge of its own. In the positive part of the paper, we show that suspending judgment, like believing and disbelieving, rests on a hinge that renders it both intelligible and justified. We develop the idea that justified suspension about ordinary propositions is explained by taking for granted that one is fallible. This view resolves the identified problems and clarifies how suspension constitutes a legitimate part of hinged epistemic rationality. It also connects hinge epistemology with debates on higher-order evidence and on reasons for suspension of judgment.