The surface microstructures of Natural Killer (NK) cells, such as microvilli, are essential for target cell recognition and the subsequent formation of immunological synapses. However, traditional cryopreservation protocols (e.g., 10% DMSO and serum) severely damage the cell surface structure, which further impairs cytotoxicity. Although a variety of novel cryoprotectants or ice inhibitors have emerged to improve the post-thaw viability of cells, there are currently few reports on strategies for the preservation of surface microstructures essential for immune synapse formation in natural killer (NK) cells. Here, we introduce a dual-protection strategy that combines the membrane-stabilizing capacity of Astragalus Polysaccharide (APS), a bioactive compound from traditional Chinese medicine, with a hydrogel encapsulation system to mitigate cryo-injury from ice crystal formation. The results demonstrated that, in the absence of DMSO, the experimental group achieved an 85% viability rate for NK-92 cells. Furthermore, the surface microstructure was significantly better preserved compared to conventional protocols, and the corresponding cytokine secretion and cytotoxicity showed no significant difference from the fresh group. This study demonstrates that the synergistic cryoprotective effect of APS and hydrogel, thereby laying a solid foundation for immune cell preservation and cell-based therapies.
This study examined the relationship between physical condition and plasmacytoid dendritic cell (pDC) activation in healthy adults who ingested Lactobacillus paragasseri SBT2055 (LG2055). This randomized, double-blind, placebo-controlled, parallel-group comparative study involved 200 participants who were randomly divided into the LG2055 and placebo groups. The participants ingested one bottle of drinkable yogurt with or without LG2055 daily for 12 weeks. A daily physical health questionnaire on local and systemic symptoms of the common cold was used as the primary outcome. The secondary outcomes were pDC activity, pDC frequency, and IFN-α production by peripheral blood mononuclear cells. Of the 200 participants, 196 completed the intake, and after excluding 8 participants, 188 (95 in the LG2055 group and 93 in the placebo group) were analyzed. The LG2055 group showed a significantly lower ratio of "with symptoms" during the intake period for nine symptoms (nasal congestion, sneezing, hoarseness, cough, headache, general malaise, chills, feverishness, and feeling unwell) (Chi-squared test, p < 0.05). Based on reports that aging correlates with numerical and functional decline in pDCs, stratified analysis was conducted and revealed that changes in the expression levels of cell surface markers (CD86, HLA-DR, and CD40) in pDCs were significantly higher in the LG2055 group among young participants (<40 years), whereas LG2055 intake suppressed changes in physical condition. In middle-aged participants (≥40 years), LG2055 neither activated pDCs nor strongly influenced their physical condition. The study results indicate that pDC activation by LG2055 contributes to the maintenance of physical condition and suggests that LG2055 improves subjective symptoms by activating pDCs. https://www.umin.ac.jp/ctr/index.htm, identifier UMIN000055950.
The interplay between cells and their surrounding microenvironment drives multiple cellular functions, including migration, proliferation, and cell fate transitions. The nucleus is a mechanosensitive organelle; however, the morphological and functional changes of the nucleus induced by a three-dimensional (3D) extracellular environment remain unclear. Here, we report that leukemia Jurkat cells selected after 3D growth conditions retain persistent nuclear changes even after being released from confinement. These altered cells showed aberrant nuclear wrinkling, visualized by the lamin B1 distribution and mediated by disrupted actin dynamics and protein kinase C (PKC)β signaling. Moreover, these cells presented changes in chromatin compaction, transcription, apoptosis, and in vivo dissemination. By combining biomechanical techniques and single-nucleus analysis, we have determined that these cells exhibit a distinct nuclear mechanical behavior and biophysical signature compared with control cells. Together, these findings demonstrate that 3D microenvironments alter leukemia cell biology by promoting persistent changes in chromatin organization, morphology, and mechanical response of the nucleus.
Conjunctival lymphoma is rare in dogs, with most cases exhibiting the B cell phenotype. Concurrent cutaneous and conjunctival T cell involvement is exceptionally uncommon. This case report describes a dog with cutaneous T-cell lymphoma that presented with chronic conjunctivitis and conjunctival T-lymphocyte infiltration. A 15-year-old spayed female Chihuahua presented with a 3-month history of bilateral conjunctivitis that was unresponsive to conventional therapy. Physical examination revealed severe conjunctival inflammation extending into the corneal limbus and perinasal depigmentation. Conjunctival cytology revealed the presence of mixed inflammatory cells. Histopathological examination of the nasal skin confirmed an epitheliotropic T-cell lymphoma with dense atypical lymphoid infiltration. Immunohistochemistry revealed CD3-positive, CD79α-negative cells. Conjunctival biopsy demonstrated lymphocytic infiltration with a similar immunophenotype, although cellular atypia was minimal and mitotic figures were rare. The patient was initially managed with topical corticosteroids, followed by oral prednisolone, and the patient survived for 191 days post-diagnosis. This case underscores the need to consider neoplastic disease in dogs presenting with chronic conjunctivitis, particularly when mucocutaneous lesions are also present. The identification of T-lymphocyte-predominant conjunctival infiltration in a dog with confirmed cutaneous T-cell lymphoma suggests either an early stage of neoplastic involvement or a reactive inflammatory process. These findings emphasize the value of careful diagnostic evaluation, including tissue biopsy and immunohistochemistry, when managing refractory ocular inflammatory conditions.
High cytotoxicity towards physiological cells and the development of drug resistance remain major challenges in anticancer therapy. The use of drug delivery systems for doxorubicin hydrochloride (DOX·HCl) aims to enhance its selective accumulation in cancer cells and reduce adverse effects on normal tissues. In this study, complexation efficiency was assessed through spectroscopic analysis and computational chemistry methods, while cytotoxicity was evaluated using in vitro assays on selected cell lines, including normal cells (CCd1079Sk) and cancerous cells (MCF-7, HeLa, and SKOV-3). The formation and stoichiometry of the inclusion complexes were investigated using UV-Vis and fluorescence spectroscopy, and the experimental data were supported by computational studies confirming the formation of 1:1 complexes. Density functional theory (DFT) calculations performed in both vacuum and DMSO environments revealed the presence of hydrogen bonding interactions that further stabilize the complexes. Importantly, the use of cholesteryl-modified cyclodextrin (CD21chol) enhanced the antiproliferative effect of DOX·HCl on cancer cells and improved the drug's selectivity toward neoplastic cells over normal cells. Overall, the CD21chol:DOX·HCl complexes exhibit favorable physicochemical and biological properties, indicating their promise as a targeted drug delivery system capable of reducing side effects and improving therapeutic outcomes in cancer treatment.
Programmed Cell Death Protein-1 (PD-1)/Programmed Cell Death-Ligand 1 (PD-L1) interaction has a crucial role in maintaining the immune system's self-tolerance by downregulating T cell activation. This mechanism is also used by several types of cancers. By overexpressing the PD-L1 protein, cancer cells can evade the immune response and, therefore, become invisible to the immune system. Herein, we present a detailed characterization of the activity of improved N-terphenylpicolinamides, a class of small molecular blockers targeting the PD-L1 protein disclosed in our recent patent and following patent applications. In our studies, we utilized a cell-based structure-activity relationship (SAR) analysis, which allowed us to discriminate the bioactivity of molecules beyond the detection limits of the protein-based HTRF assay. Our final molecules display high affinity to the molecular target and in vitro bioactivity approaching the activity of a positive control ARB-272572 molecule. An optimized molecule activates primary immune cells, leading to enhanced elimination of cancer cells, as we show in a newly developed co-culture setup. In addition, a co-crystal structure described here confirms the intended mode of binding of the small molecule to PD-L1. Our pharmacokinetics (PK) results rationalize the choice of a representative molecule for further in vivo testing.
Canine lymphoma is the most common hematopoietic malignancy, but the primary mediastinal form is rare. Progression from this form to systemic multicentric lymphoma has not been clearly documented in veterinary medicine, and optimal treatment strategies remain uncertain. This report describes a case of primary mediastinal T-cell lymphoma in a young dog that progressed to multicentric disease and was managed with chemotherapy and radiation therapy. A 2-year-old castrated male Shetland sheepdog was referred for evaluation of a cranial mediastinal mass detected on thoracic radiographs. On physical examination, bradycardia was noted, with all peripheral lymph nodes within normal limits. Laboratory abnormalities included severe hypercalcemia, elevated symmetric dimethylarginine, and the presence of large lymphocytes on blood smear. Cytology, polymerase chain reaction for antigen receptor rearrangements, and flow cytometry confirmed CD4+ T-cell mediastinal lymphoma. Initial treatment with the 25-week L-CHOP protocol achieved complete remission, but relapse occurred at Week 8, prompting radiation therapy to the mediastinal and submandibular masses. These lesions regressed but generalized peripheral lymphadenomegaly and a splenic honeycomb pattern developed, indicating progression to multicentric lymphoma. Based on ex vivo drug sensitivity testing, lomustine was initiated as rescue chemotherapy, achieving a second complete remission. Nevertheless, relapse occurred 38 d after the initial lomustine administration, and the dog ultimately died. Key clinical message: This case highlights the fact that progression from primary mediastinal to multicentric lymphoma may be associated with a poor prognosis in dogs. Radiation therapy demonstrated potential efficacy and warrants further investigation as a treatment option for canine mediastinal lymphoma. Progression d’un lymphome à cellules T primaire médiastinal vers une forme multicentrique chez un jeune chienLe lymphome canin est la tumeur maligne hématopoïétique la plus fréquente, mais sa forme primaire médiastinale est rare. La progression de cette forme vers un lymphome systémique multicentrique n’a pas été clairement documentée en médecine vétérinaire, et les stratégies thérapeutiques optimales restent incertaines. Ce rapport décrit le cas d’un jeune chien atteint d’un lymphome à cellules T primaire médiastinal ayant évolué vers une forme multicentrique et traité par chimiothérapie et radiothérapie.Un Shetland mâle castré de 2 ans a été référé pour l’évaluation d’une masse médiastinale crâniale détectée sur des radiographies thoraciques. À l’examen clinique, une bradycardie a été notée, tandis que tous les ganglions lymphatiques périphériques étaient normaux. Les anomalies des analyses de laboratoire comprenaient une hypercalcémie sévère, une élévation de la diméthylarginine symétrique et la présence de grands lymphocytes sur le frottis sanguin. La cytologie, la PCR pour les réarrangements des récepteurs d’antigènes et la cytométrie en flux ont confirmé un lymphome médiastinal à cellules T CD4+. Un traitement initial par le protocole L-CHOP de 25 semaines a permis d’obtenir une rémission complète, mais une rechute est survenue à la 8e semaine, nécessitant une radiothérapie des masses médiastinales et sous-mandibulaires. Ces lésions ont régressé, mais une lymphadénomégalie périphérique généralisée et un aspect en nid d’abeilles de la rate sont apparus, indiquant une progression vers un lymphome multicentrique. Sur la base de tests de sensibilité aux médicaments ex vivo, la lomustine a été instaurée comme chimiothérapie de rattrapage, permettant d’obtenir une seconde rémission complète. Néanmoins, une rechute est survenue 38 jours après la première administration de lomustine, et le chien est finalement décédé.Message clinique clé :Ce cas souligne le fait que la progression d’un lymphome médiastinal primaire vers un lymphome multicentrique peut être associée à un mauvais pronostic chez le chien. La radiothérapie a démontré une efficacité potentielle et justifie des recherches plus approfondies en tant qu’option thérapeutique pour le lymphome médiastinal canin.(Traduit par Dr Serge Messier).
Anion exchange membrane fuel cells (AEMFCs) have caught widespread attention as a next-generation low-cost hydrogen conversion technology. However, the AEMFC technology is still in its infancy, and there are rarely reports of cost-effective AEMFC stacks. Therefore, it is imperative yet significantly challenging to develop Pt-free, highly active, and durable hydrogen oxidation reaction (HOR) catalysts for AEMFC stack applications. Here, we present a scalable Zn single atom-gluing Ru nanoparticle on a Zn-N-C support (Ru@Zn-N-C) in which the incorporation of Zn single atoms substantially boosts H2 adsorption and stabilizes Ru nanoparticles. Consequently, the 10-g-scale Ru@Zn-N-C achieves an unprecedented peak power density (PPD) of 2.10 W cm-2 and a record-breaking anode specific power of 42 W mg-1 with an ultralow Ru loading of 0.05 mg cm-2 in a single AEMFC. Meanwhile, the rated power density of the Ru@Zn-N-C-based fuel cell (1.24 W cm-2@0.65 V in H2-air) fulfills the US Department of Energy (DOE) target for 2025 (1 W cm-2, ≤0.125 mgPGM cm-2 loading), and the fuel cell can be operated stably at 1 A cm-2 for over 200 h, significantly outperforming the state-of-the-art AEMFCs. Most importantly, we develop cost-effective three-cell AEMFC stacks that can achieve an exceptional rate power of approximately 75 W in H2-O2 with an ultralow Ru loading of 0.05 mg cm-2, which can project only 8 g Ru utilization for a 100 kW fuel cell vehicle, surpassing the ultimate US DOE target of 0.1 gPt kW-1 for urban transportation.
Panvascular diseases represent a spectrum of systemic vascular disorders driven predominantly by atherosclerosis (AS) and characterized by multi-organ involvement. Their complex spatial heterogeneity and dynamic pathophysiology pose persistent challenges for accurate visualization. Conventional imaging modalities, although clinically indispensable, often lack sufficient lesion specificity and biological adaptability to capture key disease processes. Recent advances in nanotechnology have introduced cell membrane-mimetic nanoprobes, which leverage biomimetic features such as prolonged circulation, immune evasion, and enhanced lesion targeting. These properties enable sensitive detection of critical vascular events, including endothelial activation, plaque vulnerability, and thrombus evolution across diverse vascular territories. Despite rapid technological progress, a unifying framework connecting probe engineering, imaging performance, and translational relevance remains insufficiently defined. This review systematically examines the design principles, fabrication strategies, and functional mechanisms underlying cell membrane-mimetic nanoprobes. We synthesize recent developments across major imaging platforms-including magnetic resonance imaging (MRI), positron emission tomography (PET), optical imaging, and multimodal imaging-and evaluate their roles in disease characterization. Furthermore, we discuss how biomimetic nanoprobes may facilitate risk stratification, precision diagnosis, and personalized therapeutic guidance in panvascular diseases. By integrating emerging bio-nanotechnologies with vascular imaging science, this review provides a forward-looking perspective on next-generation diagnostic strategies and their potential clinical translation.
Two-dimensional (2D) electronic materials are emerging candidates for flexible neural interfaces, yet their biocompatibility remains unclear because most studies use exfoliated flakes or suspensions. Here, we report a systematic in vitro comparison of large-area, electronics-grade, chemical-vapor-deposited graphene, MoS2, PtSe2, and PtTe2, together with flaky MoS2 and thin-film metals, as substrates for mouse neural stem cells. All large-area 2D materials support neural stem cell viability and show live-dead and metabolic readouts comparable to laminin-coated glass. Each material also supports robust neuronal differentiation, with extensive βIII-tubulin expression. Flaky MoS2 uniquely promotes strong neuronal maturation, yielding substantially higher fractions of NeuN-positive neurons, whereas PtSe2 biases differentiation toward glial lineages, including oligodendrocyte- and astrocyte-like cells. These findings establish large-area 2D materials as biocompatible, tunable platforms for neural interfacing and highlight material format as a key design variable for future bioelectronic devices.
Perovskite solar cells (PSCs) offer unique advantages for space-based energy harvesting, combining cost-effective manufacturing with flexible, high power-to-weight devices that can reduce payload mass in deployable structures. Despite this promise, few reports have demonstrated the viability of this technology in realistic, space-based scenarios, where they are subjected to large temperature variations and hard radiation. Here, we present a comprehensive analysis of PSC performance in low Earth orbit (LEO). The champion rigid cell exhibited relatively stable in-orbit performance at ∼80% of initial efficiency over a 44-day measurement interval that concluded nearly 100 days after launch, corresponding to ∼1600 orbital eclipse cycles and temperature ranges from -25 to 35°C. Mission data was systematically compared with laboratory measurements of rigid and ultrathin flexible PSCs across temperatures from -80 to +80°C and upon exposure to high-energy proton radiation. Flexible devices retained over 92% efficiency after a proton dose equivalent to 50 years in orbit. Despite this radiation tolerance, mitigating pre-flight environmental degradation remains a challenge for ultrathin substrates. Combined, this study bridges the gap between short suborbital demonstrations and long-term orbital performance, highlighting the potential of PSCs as a low-cost, resilient alternative for light harvesting, even in harsh space environments.
Sickle cell trait (SCT), historically regarded as a benign carrier state, may nonetheless be associated with severe complications such as bilateral avascular necrosis (AVN) of the femoral head in select individuals. This risk is often underrecognized, particularly in regions with high SCT prevalence, leading to delayed diagnosis and management. We report the case of a 43-year-old Yemeni man who presented with progressive bilateral hip pain over eight months without traditional risk factors except smoking. His family history was notable for sickle cell disease and trait. Physical examination revealed painful, restricted hip movement and mild splenomegaly. Laboratory testing confirmed SCT with an HbS level of 33.9% and a normal hemoglobin concentration of 16.5 g/dL. Initial radiographs were unremarkable, but MRI demonstrated bilateral femoral head AVN with marrow edema and subchondral changes. While alternative causes, including thrombophilia, were not fully excluded, conservative management was unsuccessful due to poor adherence, necessitating surgical referral. In conclusion, this case adds to emerging evidence that SCT may contribute to severe orthopedic morbidity in the presence of additional risk factors such as smoking. We advocate for a high index of suspicion for established causes of AVN and early MRI in symptomatic patients to prevent diagnostic delay and irreversible joint damage.
We present a fluorogenic cyclometalated Ir(III) probe (cIr-Q) that selectively lights up telomeric G-quadruplexes (GQs), features a large Stokes shift (∼168 nm), high photostability, rapid passive nuclear entry (≤2 min), and wash-free operation. Integrated with super-resolution microscopy, cIr-Q enables in situ quantification of higher-order telomeric architectures in living cells. NMR and biochemical assays further delineate a TERRA-initiated pathway: RNA-DNA hybridization exposes the G-rich strand to fold into GQs that facilitate t-loop formation. In a senescence model, cIr-Q reports an aging-associated decrease of GQs/t-loop signals. These results establish cIr-Q as a practical biosensing platform for live-cell readout of telomeric structural biomarkers, bridging materials design with chromosome biology without fixation or permeabilization.
Surface Enhanced Raman Spectroscopy (SERS) nanotags offer ultrahigh sensitivity and multiplexing capability over and above traditional fluorescence dyes for bioimaging but suffer from more drawbacks of more complex synthesis and measurement. Here we report a facile method to create libraries of nanotags with diverse Raman reporters for sensitive SERS labelling, whilst addressing complexity and reproducibility of synthesis that many nanotags suffer from. We create and demonstrate a library of SERS nanotags synthesized via incorporation of different thiolated and non-thiolated Raman reporters (including barcoded combinations) into silver nanoparticle (Ag NP) aggregates, mediated by water soluble cucurbit[7]uril (CB7) as a molecular glue. These controlled aggregates achieve significant SERS enhancement regardless of whether the Raman reporter possesses functional groups for metal adsorption, greatly increasing the choice of potential Raman reporters for creating libraries of SERS nanotags with massive barcoding and multiplexing depth. Further coating of the SERS nanotag aggregates with functional polyethylene glycols results in long-term stability, excellent biocompatibility, and versatile functionality to attach biomolecules. We demonstrate the utility of our SERS nanotags in fast imaging of cell-particle interactions and multiplexed ('multicolor') surface biomarker mapping at 10 ms per point using a 1.5 mW laser or less. Our method is not only simple to implement but offers flexible and reproducible libraries of SERS nanotags with great potential for a broad range of biological labelling challenges requiring sensitivity, speed and multiplexing.
This study reports the biological evaluation of novel Schiff base-tethered organoselenium (OSe) compounds as potential anticancer agents. New derivatives (HB178, HB179, HB181, HB183, HB208, HB209, and HB210) were synthesized and screened for cytotoxicity against eight cancer cell lines (including HN9, FaDu, MCF7, A375, HEPG2, HuH7, A549, and HCT116) and two normal cell lines (OEC and HSF). Among them, HB183, HB209, and HB210 exhibited the most potent growth inhibition (GI) activity, with average values of 78.25%, 76.34%, and 79.14%, respectively-surpassing the reference drug doxorubicin (61.89%). HB183 demonstrated the strongest cytotoxic effects, with IC50 values of 9.72 µM (MCF7), 13.28 µM (HCT116), 13.50 µM (A549), and 31.28 µM (HEPG2), significantly outperforming doxorubicin across multiple cell lines. Importantly, HB183 showed selective cytotoxicity with lower GI% values against normal OEC (53.90%) and HSF (42.27%) cells. Mechanistic investigations revealed that HB183 upregulated key pro-apoptotic proteins-BAX (1.39-fold), caspase-3 (1.18-fold), caspase-7 (1.20-fold), and caspase-9 (1.45-fold)-while downregulating anti-apoptotic markers such as BCL-2 (1.22-fold), MMP2 (1.15-fold), and MMP9 (1.30-fold). Furthermore, flow cytometry analysis indicated that HB183 induced cell cycle arrest at the pre-G1 phase in MCF7 cells, increasing the population from 94.32% to 98.84%. Molecular docking, molecular dynamics simulation (for 500 ns), and MM-GBSA calculations for the lead analogue (HB183) towards the BCL-2 target, as a crucial one in the pathway of apoptosis induction, were performed to support the mechanistic investigation. These findings suggest that HB183 is a promising lead for further development as a selective and potent anticancer agent, particularly in the treatment of breast cancer.
暂无摘要（点击查看详情）
Soil cadmium (Cd) contamination poses a significant threat to agricultural productivity and food safety. Although transporter genes have been extensively studied for Cd management, their manipulation often disrupts essential mineral homeostasis. This study identified the rice formin-like gene OsFH2 as a novel Cd-responsive regulator that coordinately modulates Cd tolerance and accumulation. OsFH2 was predominantly expressed in roots and panicles, and its transcription was rapidly induced by Cd stress. The OsFH2 protein localized to the cytoplasm, nucleus, and plasma membrane. Heterologous expression of OsFH2 enhanced Cd tolerance and decreased intracellular Cd accumulation in a Cd-hypersensitive yeast strain. In rice, overexpression of OsFH2 significantly improved Cd stress tolerance and seedling vigor. This improvement was associated with enhanced antioxidant enzyme activities, alongside reduced accumulation of reactive oxygen species (ROS) and levels of lipid peroxidation (as measured by malondialdehyde content). Crucially, OsFH2 overexpression enhanced Cd sequestration in the root cell wall, resulting in a 41.2 % increase in root Cd retention and a 33.7 % decrease in Cd translocation to shoots. Field trials demonstrated that OsFH2-overexpressing lines reduced grain Cd accumulation by 34 -48 % and increased yield by 12 -15 % compared to the wild type, while maintaining normal levels of manganese, zinc, and copper. RNA sequencing revealed that OsFH2 orchestrated a transcriptional program involving cell wall remodeling, phenylpropanoid biosynthesis, and antioxidant defense. We propose a model in which OsFH2, as a key organizer of the actin cytoskeleton, acts as a molecular switch that coordinates a multi-layered adaptive network. This network simultaneously enhances the physical sequestration capacity of the cell wall, reinforces the antioxidant system, and modulates metal transporters, thereby promoting selective Cd exclusion and preferential Zn allocation. Our findings establish OsFH2 as a promising genetic target for breeding Cd-resistant and high-yielding rice varieties.
Endosomes are nanoscale intracellular compartments that sort and recycle cell-surface receptors such as epidermal growth factor receptor-1 (EGFR1). Nanometer-scale interactions and coclustering of signaling proteins, cargo, and the membrane are critical to this process, yet direct 3D visualization has been hindered by the limited resolution of conventional and super-resolution microscopies. Here, we adapt expansion microscopy (ExM) to visualize and quantify nanoclusters of endosomal proteins in human retinal pigment epithelial (RPE-1) cells. We developed a 3D distortion analysis leveraging the Farneback optical-flow principle to detect anisotropies in hydrogel expansion, revealing under-expansion of cytoplasmic regions within ExM hydrogels and overestimation of size and distance measurements of small compartments such as endosomes. To calibrate ExM images of cytoplasmic regions containing endosomes, we introduced a self-assembling protein nanocage that reports the true local nanoscale expansion factor. To stimulate and visualize EGFR1 internalization and sorting, we applied a pulse-chase protocol with fluorescently tagged epidermal growth factor (EGF), fixed cells at 15 and 30 min, and subjected samples to 10-fold ExM and multiplexed 3D Airyscan microscopy to map cargo and EGFR1 relative to other endosomal proteins. A volume tracing pipeline was developed to visualize the changes in the labeled EGF and EGFR1 densities at the limiting membrane of the endosomes. These changes included enrichment of EGF and EGFR1 in the endosomal interior and accumulation of Rab5a near the limiting membrane during early endosome maturation. Together, this multiplexed 3D ExM toolkit provides a quantitative framework for visualizing and measuring small subcellular organelles at true molecular-scale resolution.
Drug-induced lung disease (DILD) is a severe adverse event of cancer treatment. Several clinical reports have demonstrated an association between DILD and tumor progression. However, the underlying mechanism remains unclear. This study aimed to elucidate the role of tumor-bearing status in the development of DILD. We prepared a subcutaneous Lewis lung carcinoma (LLC) and KLN205-bearing model. To trigger DILD, bleomycin (BLM) was administered subcutaneously. mRNA expression associated with endothelial activation (PAI-1, vWF, and ICAM-1), inflammatory cell infiltration, and alveolar wall thickness was assessed by using bronchioalveolar lavage fluid (BALF) and lung tissue. Additionally, the role of high-mobility group box 1 (HMGB1) in tumor-bearing status was examined. Compared with control mice, LLC- and KLN205-bearing mice showed a tendency toward increased expression of at least one of PAI-1, vWF, and ICAM-1 on endothelium, along with inflammatory cell infiltration in the lungs. BLM-treated mice with LLC showed more inflammatory cell infiltration than BLM-treated mice, accompanied by a significant increase in PAI-1, vWF, and ICAM-1 expression on endothelium. Moreover, BLM-treated mice with LLC exhibited pronounced alveolar wall thickening. In LLC-bearing mice, serum HMGB1 levels were significantly higher compared with control mice. Additionally, inflammatory cell infiltration in the lungs tended to be increased by the intraperitoneal injection of HMGB1, which was accompanied by increased expression of vWF and ICAM-1 on endothelium. This study showed that tumor-bearing status elicits proinflammatory activation in endothelial cells and inflammatory cell infiltration into the lungs that aggravates DILD caused by BLM.
Objective.Microstimulation delivers electrical pulses directly into the brain, with one of its promises being to restore lost senses to millions of people. Yet a fundamental challenge remains: how do intracortical microstimulation (ICMS) patterns engage neural circuits to achieve the inception of specific experiences, such as vivid sensory percepts of touch and vision? Here, we define 'inception' as the initiation of percepts evoked by microstimulation through the mapping of stimulation to circuit-level activity that results in sensory experiences.Approach.This perspective proposes an integrated research framework that combines Reverse Translation, Forward Translation, and computational neuroscience to bridge insights between clinical observations and high-resolution animal studies.Framework.Our framework envisions the development and evaluation of ICMS strategies within a cross-species system that narrows the range of plausible underlying neural mechanisms and the set of evoked perceptual outcomes. Reverse Translation uses human perceptual reports about phosphenes, tones, and touch to guide investigations in rodents and non-human primates, mapping the cell types and circuits underlying each percept. Forward Translation leverages these biological insights to design refined ICMS protocols for selective circuit engagement. Bidirectional Translation weaves these approaches together through computational neuroscience, ensuring that experimental observations iteratively and continuously refine one another across species and experimental modalities.Significance.This integrated strategy aims to transform microstimulation research into a dynamic dialogue between fundamental science and human experience. Harnessing the Bidirectional Translation Framework can accelerate therapies that enhance quality of life for people with sensory or motor impairments, and contribute more broadly to systems neuroscience by uncovering the mechanisms by which causal manipulation changes activity in neurons and networks.