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During recovery from septic shock, circulating mitochondrial N-formyl peptides (mtFPs) predispose to secondary infection by occupying formyl peptide receptor 1 (FPR1) on the neutrophil (polymorphonuclear leukocyte, PMN) membrane, suppressing cytosolic calcium ([Ca2+]i)-dependent responses to secondarily encountered bacteria. However, no study has yet investigated therapeutic clearance of circulating mtFPs in clinical settings. Thus, we studied how to remove mtFPs from septic-shock plasma and whether such removal could preserve cell-surface FPR1 and restore sepsis-induced PMN dysfunction by normalizing [Ca2+]i flux. In in vitro model systems, mtFP removal rescued PMN FPR1-mediated [Ca2+]i flux and chemotaxis that had been suppressed by prior mtFP exposure. However, PMN functional recovery occurred in a stepwise fashion over 30 - 90 minutes. Intracellular Ca2+-calmodulin appears to contribute to this delay. In ex vivo model systems using blood samples obtained from patients with septic shock, anti-mtFP antibodies alone failed to eliminate mtFPs from septic-shock plasma or inhibit mtFP activity. We therefore created a beads-based anti-mtFP antibody cocktail (bb-AMfpA) by combining protein A/sepharose with antibodies specific for the most potent human mtFP chemoattractants. The bb-AMfpA treatment successfully removed those active mtFPs from septic-shock plasma. Furthermore, the bb-AMfpA treatment significantly restored chemotactic and bactericidal dysfunction of PMNs obtained from patients with septic shock who developed secondary infections. By clearing circulating mtFPs, the immobilized anti-mtFP antibody therapy prevented mtFP interactions with surface FPR1, thereby restoring [Ca2+]i-dependent PMN antimicrobial function in clinical septic-shock environments. This approach may help prevent the development of secondary, nosocomial infections in patients recovering from septic shock.
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AIM OF THE STUDY: We evaluated whether an artificial intelligence (AI)-driven robot cardiopulmonary resuscitation (CPR) could improve hemodynamic parameters and clinical outcomes. METHODS: We developed an AI-driven CPR robot which utilizes an integrated feedback system with an AI model predicting carotid blood flow (CBF). Twelve pigs were assigned to the AI robot group (n = 6) and the LUCAS 3 group (n = 6). They underwent 6 minutes of CPR after 7 minutes of ventricular fibrillation. In the AI robot group, the robot explored for the optimal compression position, depth and rate during the first 270-second period, and continued CPR with the optimal setup during the next 90-second period and beyond. The primary outcome was CBF during the last 90-second period. The secondary outcomes were coronary perfusion pressure (CPP), end-tidal carbon dioxide level (ETCO2) and return of spontaneous circulation (ROSC). RESULTS: The AI model's prediction performance was excellent (Pearson correlation coefficient = 0.98). CBF did not differ between the two groups [estimate and standard error (SE), -23.210 ± 20.193, P = 0.250]. CPP, ETCO2 level and rate of ROSC also did not show difference [estimate and SE, -0.214 ± 7.245, P = 0.976 for CPP; estimate and SE, 1.745 ± 3.199, P = 0.585 for ETCO2; 5/6 (83.3%) vs. 4/6 (66.7%), P = 1.000 for ROSC). CONCLUSION: This study provides proof of concept that an AI-driven CPR robot in porcine cardiac arrest is feasible. Compared to a LUCAS 3, an AI-driven CPR robot produced comparable hemodynamic and clinical outcomes.
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Air pollution, a global health concern, has been associated with adverse effects on human health. In particular, particulate matter (PM), which is a major contributor to air pollution, impacts various organ systems including the skins. In fact, PM has been suggested as a culprit for accelerating skin aging and pigmentation. In this study, using single-cell RNA sequencing, IL-24 was found to be highly upregulated among the differentially expressed genes commonly altered in keratinocytes and fibroblasts of ex vivo skins exposed to PM. It was verified that PM exposure triggered the expression of IL-24 in keratinocytes, which subsequently led to a decrease in type I procollagen expression and an increase in MMP1 expression in fibroblasts. Furthermore, long-term treatment of IL-24 induced cellular senescence in fibroblasts. Through high-throughput screening, we identified chemical compounds that inhibit the IL-24-STAT3 signaling pathway, with lovastatin being the chosen candidate. Lovastatin not only effectively reduced the expression of IL24 induced by PM in keratinocytes but also exhibited a capacity to restore the decrease in type I procollagen and the increase in MMP1 caused by IL-24 in fibroblasts. This study provides insights into the significance of IL-24, illuminating mechanisms behind PM-induced skin aging, and proposes IL-24 as a promising target to mitigate PM-associated skin aging.
Subject(s)
Fibroblasts , Interleukins , Keratinocytes , Particulate Matter , Skin Aging , Skin Aging/drug effects , Particulate Matter/toxicity , Interleukins/metabolism , Interleukins/genetics , Keratinocytes/drug effects , Fibroblasts/drug effects , Humans , Cellular Senescence/drug effects , Signal Transduction/drug effects , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 1/metabolism , STAT3 Transcription Factor/metabolism , Skin/drug effects , Air Pollutants/toxicityABSTRACT
Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), or IL-13, but not IL-4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL-13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis-like inflammation and IL-17A, while activating LXR or PPARγ inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL-13-producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.
Subject(s)
Autoimmunity , Liver X Receptors , PPAR gamma , Skin , Animals , Skin/immunology , Skin/metabolism , Skin/pathology , Humans , Liver X Receptors/metabolism , Mice , PPAR gamma/metabolism , Psoriasis/immunology , Psoriasis/pathology , Psoriasis/metabolism , Mice, Inbred C57BL , Interleukin-13/metabolism , STAT6 Transcription Factor/metabolism , Immunity, Innate , Male , Female , Lymphocytes/immunology , Lymphocytes/metabolismABSTRACT
BACKGROUND: Atopic dermatitis (AD), a chronic inflammatory skin disease with T cell activation as a key feature, in which Th2 cell-mediated responses play a pivotal role. Regulatory T cells (Treg) are central immune cells that restrict autoimmunity and inflammation in the body. Patients with immune dysregulation, polyendocrinopathy, or enteropathy X-linked syndrome, an immune disease characterized by a deficiency in Treg, develop skin inflammation and allergic disorders, indicating that Treg play a crucial role in the development of allergic skin inflammation. OBJECTIVE: we investigated the underlying mechanisms by which Treg control cutaneous allergic inflammation. METHODS: An allergic skin inflammation mouse model was constructed using MC903, and Treg-depleted mouse model was constructed using diphtheria toxin. Neutralization of IFN-γ was constructed using anti-mouse-IFN-γ mouse antibody. Neutrophil infiltration was analyzed by flow cytometry and immunohistochemistry. Neutrophil extracellular traps (NETs), a process called NETosis, were detected using immunofluorescence. In vitro neutrophil stimulation and immunocytochemistry was conducted to demonstrate the effect of IFN-γ on NETosis. RESULTS: The depletion of Foxp3+ Treg led to significantly exacerbated AD-like skin inflammation, including increased recruitment of neutrophils and expression of Th1 cytokine IFN-γ. Neutrophil infiltrating in skin of Treg-depleted mice released more NETs than wild type. Neutralization of IFN-γ abolished neutrophil infiltration and NETosis in Treg-depleted mice. Neutrophils stimulated with IFN-γ were more prone to release NETs in vitro. Finally, Foxp3+ Treg control cutaneous allergic inflammation by regulating IFN-γ-driven neutrophilic infiltration and NETosis. CONCLUSION: Our results highlight the previously underestimated Treg-IFN-γ-neutrophil inflammatory axis.
Subject(s)
Dermatitis, Atopic , Disease Models, Animal , Extracellular Traps , Forkhead Transcription Factors , Interferon-gamma , Neutrophil Infiltration , Neutrophils , Skin , T-Lymphocytes, Regulatory , Animals , T-Lymphocytes, Regulatory/immunology , Interferon-gamma/metabolism , Interferon-gamma/immunology , Forkhead Transcription Factors/metabolism , Mice , Extracellular Traps/immunology , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Dermatitis, Atopic/chemically induced , Skin/immunology , Skin/pathology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Neutrophils/metabolism , Humans , Mice, Inbred C57BL , FemaleABSTRACT
Aging-related bone loss is driven by various biological factors, such as imbalanced bone metabolism from decreased osteoblast and increased osteoclast activities. Various transcriptional and post-transcriptional factors increase osteoclast activity with aging; however, studies regarding the post-translational regulators of osteoclast activity are still limited. The ubiquitin E3 ligase Pellino-1 is a well-known post-translational regulator of inflammation. However, how Pellino-1 expression regulation affects osteoclast differentiation remains unclear. This study determined that Pellino-1 levels are reduced in bone marrow monocytes (BMMs) from 40-week-old mice compared to 4-week-old mice. Interestingly, conditional Knockout (cKO) of Pellino-1 in 6-week-old mice resulted in decreased bone mass, reduced body size, and lower weight than in Pellino-1 floxed mice; however, these differences are not observed in 20-week-old mice. The increased number of tartrate-resistant acid phosphatase (TRAP)-positive cells and serum levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, in 6-week-old Pellino-1 cKO mice implied a connection between Pellino-1 and the osteoclast population. Enhanced TRAP activity and upregulation of osteoclast genes in BMMs from the cKO mice indicate that Pellino-1 deletion affects osteoclast differentiation, leading to decreased bone mass and heightened osteoclast activity. Thus, targeting Pellino-1 could be a potential gene therapy for managing and preventing osteoporosis.
Subject(s)
Bone Resorption , Mice, Knockout , Osteoclasts , Ubiquitin-Protein Ligases , Animals , Osteoclasts/metabolism , Mice , Bone Resorption/metabolism , Bone Resorption/genetics , Bone Resorption/pathology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Aging/metabolism , Aging/genetics , Cell Differentiation , Osteoporosis/genetics , Osteoporosis/metabolism , Osteoporosis/pathology , Male , Mice, Inbred C57BL , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nuclear Proteins/deficiencyABSTRACT
In general, sanding robots that move as if drawing a line along a surface are mainly used when sanding objects with a large area; however, they require a long working time, and it is difficult to secure a uniform sanded area. This study focuses on large-area sanding robots, such as those for ships, storage tanks, and tank lorries, and proposes an adaptive belt tension robot equipped with a 4-point supported belt mechanism capable of sanding variable curved surfaces. In addition, a sanding normal force prediction formula is proposed to describe the sanding performance of the contact surface. This equation consists of the concentrated load function due to the belt movement and the normal force due to the vertical and horizontal elongation of the belt. A video image analysis was performed to calculate the sanding area. Therefore, we determined whether the area was uniformly sanded. The dimensions of the test bench (W × D × H) were 1700 mm × 1450 mm × 900 mm. Experiments were performed using the proposed techniques on convex specimens with radii of 725, 1000, and 2100 mm. The sanding performance was improved by 43 % compared with that of a general belt-sanding robot.
Subject(s)
Carcinoma, Squamous Cell , Maxillary Sinus Neoplasms , Humans , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/surgery , Maxillary Sinus Neoplasms/pathology , Maxillary Sinus Neoplasms/diagnostic imaging , Maxillary Sinus Neoplasms/surgery , Male , Tomography, X-Ray Computed , Cholesteatoma/surgery , Cholesteatoma/pathology , Cholesteatoma/diagnostic imaging , Middle Aged , FemaleABSTRACT
The purpose of study was to evaluate that kallistatin deficiency causes excessive production of reactive oxygen species and exacerbates neuronal injury after cardiac arrest. For in vitro study, kallistatin knockdown human neuronal cells were given ischemia-reperfusion injury, and the oxidative stress and apoptosis were evaluated. For clinical study, cardiac arrest survivors admitted to the ICU were divided into the good (CPC 1-2) and poor (CPC 3-5) 6-month neurological outcome groups. The serum level of kallistatin, Nox-1, H2O2 were measured. Nox-1 and H2O2 levels were increased in the kallistatin knockdown human neuronal cells with ischemia-reperfusion injury (p < 0.001) and caspase-3 was elevated and apoptosis was promoted (SERPINA4 siRNA: p < 0.01). Among a total of 62 cardiac arrest survivors (16 good, 46 poor), serum kallistatin were lower, and Nox-1 were higher in the poor neurological group at all time points after admission to the ICU (p = 0.013 at admission; p = 0.020 at 24 h; p = 0.011 at 72 h). At 72 h, H2O2 were higher in the poor neurological group (p = 0.038). Kallistatin deficiency exacerbates neuronal ischemia-reperfusion injury and low serum kallistatin levels were associated with poor neurological outcomes in cardiac arrest survivors.
Subject(s)
Heart Arrest , Reperfusion Injury , Serpins , Humans , Hydrogen PeroxideABSTRACT
BACKGROUND: Psoriasis is a chronic inflammatory skin disease with a Th17-skewed immune phenotype. Although it has been generally accepted that regulatory T cells (Tregs) in lesional psoriatic skin have functional impairment due to the local inflammatory microenvironment, the molecular properties of skin-homing psoriatic Tregs have not been well explored. METHODS: We designed an extensive 39 marker mass cytometry (CyTOF) panel to deeply profile the immune landscape of skin-homing Tregs from 31 people with psoriasis stratified by psoriasis area severity index score as mild (n = 15) to moderate-severe (n = 16) and 32 healthy controls. We further validated the findings with an in-vitro chemokine-mediated Treg migration assay, immunofluorescent imaging of normal and psoriatic lesional skin and analysed public single-cell RNA-sequencing datasets to expand upon our findings into the local tissue microenvironments. FINDINGS: We discovered an overall decrease in CLAhi Tregs and specifically, CLAhiCCR5+ Tregs in psoriasis. Functional markers CD39 and FoxP3 were elevated in psoriatic Tregs. However, CCR7 expression was significantly increased while CCR4 and CLA expression was reduced in psoriatic Tregs and CLAhi Tregs, which was associated with disease severity. Moreover, psoriatic Tregs revealed increased migratory capacity towards CCR7's ligands, CCL19/CCL21. Interrogation of public single-cell RNA sequencing data confirmed reduced expression of skin-trafficking markers in lesional-skin Tregs compared to non-lesioned skin, further substantiated by immunofluorescent staining. INTERPRETATION: Psoriatic circulating Tregs showed an impaired skin-trafficking phenotype thus leading to insufficient suppression of ongoing inflammation in the lesional skin, expanding upon our current understanding of the impairment of Treg-mediated immunosuppression in psoriasis. FUNDING: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and Information and Communications Technology (2020R1C1C1014513, 2021R1A4A5032185, 2020R1F1A1073692); and the new faculty research seed money grant of Yonsei University College of Medicine for 2021 (2021-32-0033).
Subject(s)
Psoriasis , T-Lymphocytes, Regulatory , Humans , Receptors, CCR7/metabolism , Psoriasis/metabolism , Skin/metabolism , Th17 CellsABSTRACT
BACKGROUND: User engagement is crucial for digital therapeutics (DTx) effectiveness; due to variations in the conceptualization of engagement and intervention design, assessment and retention of engagement remain challenging. OBJECTIVE: We investigated the influence of the perceived acceptability of experimental intervention components and satisfaction with core intervention components in DTx on user engagement, while also identifying potential barriers and facilitators to user engagement. METHODS: We conducted a mixed methods study with a 2 × 2 factorial design, involving 12 outpatients with atopic dermatitis. Participants were randomized into 4 experimental groups based on push notification ("basic" or "advanced") and human coach ("on" or "off") experimental intervention components. All participants engaged in self-monitoring and learning courses as core intervention components within an app-based intervention over 8 weeks. Data were collected through in-app behavioral data, physician- and self-reported questionnaires, and semistructured interviews assessed at baseline, 4 weeks, and 8 weeks. Descriptive statistics and thematic analysis were used to evaluate user engagement, perceived acceptability of experimental intervention components (ie, push notification and human coach), satisfaction with core intervention components (ie, self-monitoring and learning courses), and intervention effectiveness through clinical outcomes. RESULTS: The primary outcome indicated that group 4, provided with "advanced-level push notifications" and a "human coach," showed higher completion rates for self-monitoring forms and learning courses compared to the predetermined threshold of clinical significance. Qualitative data analysis revealed three key themes: (1) perceived acceptability of the experimental intervention components, (2) satisfaction with the core intervention components, and (3) suggestions for improvement in the overall intervention program. Regarding clinical outcomes, the Perceived Stress Scale and Dermatology Life Quality Index scores presented the highest improvement in group 4. CONCLUSIONS: These findings will help refine the intervention and inform the design of a subsequent randomized trial to test its effectiveness. Furthermore, this design may serve as a model for broadly examining and optimizing overall engagement in DTx and for future investigation into the complex relationship between engagement and clinical outcomes. TRIAL REGISTRATION: Clinical Research Information Service KCT0007675; http://tinyurl.com/2m8rjrmv.
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BACKGROUND: Recently, we developed a chest compression device that can move the chest compression position without interruption during CPR and be remotely controlled to minimize rescuer exposure to infectious diseases. The purpose of this study was to compare its performance with conventional mechanical CPR device in a mannequin and a swine model of cardiac arrest. MATERIALS AND METHODS: A prototype of a remote-controlled automatic chest compression device (ROSCER) that can change the chest compression position without interruption during CPR was developed, and its performance was compared with LUCAS 3 in a mannequin and a swine model of cardiac arrest. In a swine model of cardiac arrest, 16 male pigs were randomly assigned into the two groups, ROSCER CPR (n = 8) and LUCAS 3 CPR (n = 8), respectively. During 5 minutes of CPR, hemodynamic parameters including aortic pressure, right atrial pressure, coronary perfusion pressure, common carotid blood flow, and end-tidal carbon dioxide partial pressure were measured. RESULTS: In the compression performance test using a mannequin, compression depth, compression time, decompression time, and plateau time were almost equal between ROSCER and LUCAS 3. In a swine model of cardiac arrest, coronary perfusion pressure showed no difference between the two groups (p = 0.409). Systolic aortic pressure and carotid blood flow were higher in the LUCAS 3 group than in the ROSCER group during 5 minutes of CPR (p < 0.001, p = 0.008, respectively). End-tidal CO2 level of the ROSCER group was initially lower than that of the LUCAS 3 group, but was higher over time (p = 0.022). A Kaplan-Meier survival analysis for ROSC also showed no difference between the two groups (p = 0.46). CONCLUSION: The prototype of a remote-controlled automated chest compression device can move the chest compression position without interruption during CPR. In a mannequin and a swine model of cardiac arrest, the device showed no inferior performance to a conventional mechanical CPR device.
Subject(s)
Cardiopulmonary Resuscitation , Heart Arrest , Male , Animals , Swine , Pilot Projects , Manikins , Heart Arrest/therapy , Pressure , HemodynamicsABSTRACT
Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood.
Subject(s)
Dermatitis, Atopic , Thymic Stromal Lymphopoietin , Humans , Adult , Infant, Newborn , Immunity, Innate , Lymphocytes , Cytokines/metabolism , Skin/metabolism , InflammationABSTRACT
ABSTRACT: Objective: This study aimed to test whether the prognostic value of tryptophanyl-tRNA synthetase 1 (WARS1) for 28-day mortality in patients with sepsis was affected by monocytopenia. Methods: A prospective analysis of retrospectively collected samples from 74 sepsis patients was performed. WARS1, C-reactive protein (CRP), and procalcitonin were measured at admission and 24 and 72 h after admission. The prognostic value of WARS1, CRP, and procalcitonin for 28-day mortality was compared using repeated measures analysis of variance and the area under the receiver operating characteristic curve (AUROC). All analyses were performed in patients with or without monocytopenia, defined as an absolute monocyte count less than 0.1 × 10 9 cells/L. Results: WARS1 levels differed significantly between survivors and nonsurvivors when all patients and patients without monocytopenia were assessed ( P = 0.008, P < 0.001, respectively). In contrast, the WARS1 level did not differ between survivors and nonsurvivors with monocytopenia. C-reactive protein and procalcitonin levels were not different between survivors and nonsurvivors regardless of whether they had monocytopenia. The AUROCs of WARS1 at admission and 24 h for mortality were significantly higher in patients without monocytopenia (0.830, 0.818) than in patients with monocytopenia (0.232, 0.196; P < 0.001, both). When patients without monocytopenia were analyzed, the AUROCs of WARS1 for mortality were 0.830 and 0.818 at admission and 24 h, respectively, which were significantly higher than those of CRP (0.586, 0.653) and procalcitonin (0.456, 0.453) at the same time points ( P = 0.024 and 0.034, respectively). Conclusion: WARS1 is a useful biomarker for prognosis in sepsis patients without monocytopenia.
Subject(s)
Sepsis , Tryptophan-tRNA Ligase , Humans , Prognosis , C-Reactive Protein/metabolism , Procalcitonin , Retrospective Studies , Biomarkers , ROC CurveABSTRACT
Dendritic cells (DCs) are readily generated from the culture of mouse bone marrow (BM) treated with either granulocyte macrophage-colony stimulating factor (GM-CSF) or FMS-like tyrosine kinase 3 ligand (FLT3L). CD11c+MHCII+ or CD11c+MHCIIhi cells are routinely isolated from those BM cultures and generally used as in vitro-generated DCs for a variety of experiments and therapies. Here, we examined CD11c+ cells in the BM culture with GM-CSF or FLT3L by staining with a monoclonal antibody 2A1 that is known to recognize mature or activated DCs. Most of the cells within the CD11c+MHCIIhi DC gate were 2A1+ in the BM culture with GM-CSF (GM-BM culture). In the BM culture with FLT3L (FL-BM culture), almost of all the CD11c+MHCIIhi cells were within the classical DC2 (cDC2) gate. The analysis of FL-BM culture revealed that a majority of cDC2-gated CD11c+MHCIIhi cells exhibited a 2A1-CD83-CD115+CX3CR1+ phenotype, and the others consisted of 2A1+CD83+CD115-CX3CR1- and 2A1-CD83-CD115-CX3CR1- cells. According to the antigen uptake and presentation, morphologies, and gene expression profiles, 2A1-CD83-CD115-CX3CR1- cells were immature cDC2s and 2A1+CD83+CD115-CX3CR1- cells were mature cDC2s. Unexpectedly, however, 2A1-CD83-CD115+CX3CR1+ cells, the most abundant cDC2-gated MHCIIhi cell subset in FL-BM culture, were non-DCs. Adoptive cell transfer experiments in the FL-BM culture confirmed that the cDC2-gated MHCIIhi non-DCs were precursors to cDC2s, i.e., MHCIIhi pre-cDC2s. MHCIIhi pre-cDC2s also expressed the higher level of DC-specific transcription factor Zbtb46 as similarly as immature cDC2s. Besides, MHCIIhi pre-cDC2s were generated only from pre-cDCs and common DC progenitor (CDP) cells but not from monocytes and common monocyte progenitor (cMoP) cells, verifying that MHCIIhi pre-cDC2s are close lineage to cDCs. All in all, our study identified and characterized a new cDC precursor, exhibiting a CD11c+MHCIIhiCD115+CX3CR1+ phenotype, in FL-BM culture.
Subject(s)
Bone Marrow , Histocompatibility Antigens Class II , Mice , Animals , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , CX3C Chemokine Receptor 1/metabolism , Bone Marrow Cells , Dendritic Cells , Cell Differentiation , Receptor Protein-Tyrosine Kinases/metabolismABSTRACT
BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.METHODSSkin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed.RESULTSWe demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-ß stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus.CONCLUSIONThrough this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.TRIAL REGISTRATIONClinicalTrials.gov NCT04509570.FUNDINGThis work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).
Subject(s)
Autoimmune Diseases , Pemphigus , Humans , Adrenal Cortex Hormones , Autoantibodies , Autoimmune Diseases/drug therapy , Blister/drug therapy , CD4-Positive T-Lymphocytes , Chemokine CXCL13 , Desmoglein 3 , Pemphigus/drug therapyABSTRACT
Superhydrophobic surfaces, i.e., surfaces with a water contact angle (WCA) ≥ 150°, have gained much attention as they are multifunctional surfaces with features such as self-cleaning, which can be useful in various applications such as those requiring waterproof and/or protective films. In this study, we prepared a solution from recycled polyethylene terephthalate (PET) and fabricated a superhydrophobic surface using electrospinning and electrospraying processes. We observed that the fabricated geometry varies depending on the solution conditions, and based on this, we fabricated a hierarchical structure. From the results, the optimized structure exhibited a very high WCA (>156.6°). Additionally, our investigation into the self-cleaning functionality and solar panel efficiency of the fabricated surface revealed promising prospects for the production of superhydrophobic surfaces utilizing recycled PET, with potential applications as protective films for solar panels. Consequently, this research contributes significantly to the advancement of environmentally friendly processes and the progress of recycling technology.
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Although vertical configurations for high-density storage require challenging process steps, such as etching high aspect ratios and atomic layer deposition (ALD), they are more affordable with a relatively simple lithography process and have been employed in many studies. Herein, the potential of memristors with CMOS-compatible 3D vertical stacked structures of Pt/Ti/HfOx/TiN-NCs/HfOx/TiN is examined for use in neuromorphic systems. The electrical characteristics (including I-V properties, retention, and endurance) were investigated for both planar single cells and vertical resistive random-access memory (VRRAM) cells at each layer, demonstrating their outstanding non-volatile memory capabilities. In addition, various synaptic functions (including potentiation and depression) under different pulse schemes, excitatory postsynaptic current (EPSC), and spike-timing-dependent plasticity (STDP) were investigated. In pattern recognition simulations, an improved recognition rate was achieved by the linearly changing conductance, which was enhanced by the incremental pulse scheme. The achieved results demonstrated the feasibility of employing VRRAM with TiN nanocrystals in neuromorphic systems that resemble the human brain.
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Correction for 'Synaptic plasticity and non-volatile memory characteristics in TiN-nanocrystal-embedded 3D vertical memristor-based synapses for neuromorphic systems' by Seyeong Yang et al., Nanoscale, 2023, https://doi.org/10.1039/D3NR01930F.