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Purpose: To evaluate the therapeutic efficacy of topical application of a neurokinin-1 receptor (NK1R) antagonist in a rabbit model of nonallergic ocular redness. Methods: Nonallergic ocular redness was induced in rabbits by a single, topical application of dapiparzole hydrochloride eye drops (0.5%, 1%, 2%, or 5%). The NK1R antagonist L-703,606 was topically applied to the eye at the same time of induction or 20 min after induction, and phosphate buffered saline (PBS) treatment served as the control. Superior bulbar conjunctival images were taken every 30 s for the first 2 min, followed by every 4 min for 8 min, and then every 10 min until 1 h. The severity of ocular redness was evaluated on the images using ImageJ-based ocular redness index (ORI) calculations. Results: The ORI scores were significantly increased after the application of 0.5%, 1%, 2%, or 5% dapiparzole at each time point evaluated, with the most severe redness induced by the 5% dapiprazole that led to a maximal mean increase in ORI score of 14 at 20 min post-induction and thus used for subsequent evaluation of therapeutic efficacy of NK1R antagonism. Topical L-703,606, when applied at the same time as dapiprazole induction, significantly suppressed the increase of ORI scores at all time points (∼40% decrease). Furthermore, when applied at 20 min after dapiprazole induction, L-703,606 rapidly and effectively suppressed the increase of ORI scores at 30, 40, 50, and 60 min (∼30% decrease). Conclusions: Topical blockade of NK1R effectively prevents and alleviates nonallergic ocular redness in a novel animal model. [ABSTRACT FROM AUTHOR]

CD4+CD25+Foxp3+ Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3+ Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17+ or IFNγ+ 'exFoxp3' T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1- peripherally-derived Tregs are particularly susceptible to conversion to IL-17+/IFNγ+ exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.

Electrosynthesis of hydrogen peroxide (H2O2) based on proton exchange membrane (PEM) reactor represents a promising approach to industrial‐level H2O2 production, while it is hampered by the lack of high‐efficiency electrocatalysts in acidic medium. Herein, we present a strategy for the specific oxygen functional group (OFG) regulation to promote the H2O2 selectivity up to 92 % in acid on cobalt‐porphyrin molecular assembled with reduced graphene oxide. In situ X‐ray adsorption spectroscopy, in situ Raman spectroscopy and Kelvin probe force microscopy combined with theoretical calculation unravel that different OFGs exert distinctive regulation effects on the electronic structure of Co center through either remote (carboxyl and epoxy) or vicinal (hydroxyl) interaction manners, thus leading to the opposite influences on the promotion in 2e− ORR selectivity. As a consequence, the PEM electrolyzer integrated with the optimized catalyst can continuously and stably produce the high‐concentration of ca. 7 wt % pure H2O2 aqueous solution at 400 mA cm−2 over 200 h with a cell voltage as low as ca. 2.1 V, suggesting the application potential in industrial‐scale H2O2 electrosynthesis. [ABSTRACT FROM AUTHOR]

Introduction. Rosacea is a common chronic inflammatory skin disease of the central facial skin with unknown origin, significantly impacting quality of patient's life and causing various psychosocial problems. Erythematotelangiectatic rosacea (ETR) is characterized by paroxysmal flushing that occurs repeatedly and is easily resistant to therapeutic drugs. While microinjection of type A botulinum toxin (BTX) can treat ETR, there is no consensus on the injection dose, and strong evidence to verify its efficacy and safety is lacking. This randomized, double‐blind, split‐face clinical study aimed to investigate the efficacy, safety, and optimal dose of two different single‐point injection doses (0.5 U and 1 U) of BTX in the treatment of rosacea. Methods. Twenty‐six patients with ETR were randomly assigned to receive different single‐point injections of BTX (0.5 U and 1 U, respectively) every 1 cm on one half of the face. The Clinical Erythema Score (CEA), VISIA red area absolute value, Global Aesthetic Improvement Scale Score (GAIS), and recurrence at 12‐week follow‐up were evaluated at baseline, 2,4, 8, and 12 weeks after injection. Additionally, the Dermatological Quality of Life Index (DLQI) questionnaire survey and adverse reactions were also recorded. Results. All twenty‐six patients completed the follow‐up visits and were included in the analysis. Compared to the 0.5 UBTX‐treated side, the CEA score showed significantly improvement in erythema and flushing at 2, 4, and 8 weeks after injection on the 1 U BTX‐treated side (P < 0.05). The mean absolute value of the red area of VISIA was ‐19.12 ± 51.91 on 1 U BTX‐treated side and 2.5 ± 42.08, on 0.5 UBTX‐treated side at 4 weeks after treatment, showing significant improvement on the 1 U side (P < 0.05). GAIS and DLQI were also significantly improved from Week 4 to Week 12 and Week 2 to Week 12, respectively (P < 0.05). There was no recurrence of symptoms with either 0.5 U or 1 U injection by 12 weeks. Apart from one patient who experienced facial tightness and three patients who had temporary aggravation of erythema, all of which resolved without treatment, 22 patients did not report any side effects except for injection pain during the procedure. Conclusions. BTX‐A can significantly improves symptoms and quality of life in patients with refractory rosacea with few side effects. A single‐point injection of 1 U was more effective. This trial is registered with NCT06282679. [ABSTRACT FROM AUTHOR]

BackgroundCorneal allograft survival dramatically decreases in hosts with inflamed or vascularized recipient beds. We have previously shown that in rejected corneal allografts regulatory T cells (Treg) demonstrate diminished Foxp3 expression and immunoregulatory function. Treatment with low doses of IL-2 selectively expands Treg and has been proposed for the treatment of autoimmune diseases. In this study, we investigated the effect of low-dose IL-2 administration on Treg function and corneal allograft survival.MethodsAllogeneic corneal transplantation was performed on inflamed host beds. Low-dose systemic IL-2 was administered starting 3 days before grafting until 6 weeks after transplantation. Frequencies of Treg and their immunosuppressive function and antigen specificity were assessed using flow cytometry, in vitro proliferation assays, and adoptive transfer experiments. Frequencies of effector T cells (Teff) and graft infiltrating immune cells were measured at 2 weeks posttransplantation. Long-term allograft survival was evaluated for up to 9 weeks using Kaplan-Meier survival analysis.ResultsTreatment with low-dose IL-2 significantly increased frequencies of CD4CD25Foxp3 Treg and their immunosuppressive function. It also suppressed alloimmune response as shown by the decreased CD4 IFNγ T cell frequencies and graft infiltration of CD45 and CD4 cells. Clinical evaluation of the grafts showed significant improvement in long-term corneal allograft survival in the IL-2 treated group compared with controls.ConclusionsOur study is the first to report that treatment with low-dose IL-2 increases survival of corneal allografts. We propose that IL-2-mediated Treg expansion can be an effective tool to prevent alloimmunity and to improve long-term allograft survival in transplantation.

We investigate the impact of left-behind experiences on the urban identity of new-generation migrant workers using data from the 2017 China Migrants Dynamic Survey. The results show the following: (1) The left-behind experience is an important factor undermining the urban identity of new-generation migrant workers, and the conclusion remains consistent after robustness checks, such as propensity score matching. (2) Left-behind experiences of both parents away from home had the most significant negative impact on urban identity. (3) The results of the mechanism tests indicate that the left-behind experience exerts an adverse impact on urban identity through the pathways of poorer physical health, more frequent migration, more challenging job search, and stronger dependence on preexisting social networks. The findings of this study also offer policy suggestions for promoting the urban identity of new-generation migrant workers. [ABSTRACT FROM AUTHOR]

Macrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the KCa1.1 or BK channel, in regulating neurotransmitter release and smooth muscle contraction is well known, its potential involvement in immune regulation remains unclear. We employed BK-knockout macrophages and noted that the absence of a BK channel promotes the polarization of macrophages towards a pro-inflammatory phenotype known as M1 macrophages. Specifically, the absence of the BK channel resulted in a significant increase in the secretion of the pro-inflammatory cytokine IL-6 and enhanced the activity of extracellular signal-regulated kinases 1 and 2 (Erk1/2 kinases), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the transcription factor ATF-1 within M1 macrophages. Additionally, the lack of the BK channel promoted the activation of the AIM2 inflammasome without affecting the activation of the NLRC4 and NLRP3 inflammasomes. To further investigate the role of the BK channel in regulating AIM2 inflammasome activation, we utilized BK channel inhibitors, such as paxilline and iberiotoxin, along with the BK channel activator NS-11021. Pharmacological inactivation of the BK channel increased, and its stimulation inhibited IL-1β production following AIM2 inflammasome activation in wild-type macrophages. Moreover, wild-type macrophages displayed increased calcium influx when activated with the AIM2 inflammasome, whereas BK-knockout macrophages did not due to the impaired extracellular calcium influx upon activation. Furthermore, under conditions of a calcium-free medium, IL-1β production following AIM2 inflammasome activation was increased in both wild-type and BK-knockout macrophages. This suggests that the BK channel is required for the influx of extracellular calcium in macrophages, thus limiting AIM2 inflammasome activation. In summary, our study reveals a regulatory role of the BK channel in macrophages under inflammatory conditions. [ABSTRACT FROM AUTHOR]