Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of Type 1 Diabetes.

Aims/hypothesis: Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death-1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesized that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death. Methods: Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry, and ELISA. EV PD-L1: PD-1 binding was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8 T cells. Plasma EV and soluble PD-L1 were assayed in plasma of individuals with islet autoantibody positivity (Ab+) or recent-onset type 1 diabetes and compared to non-diabetic controls. Results: PD-L1 protein colocalized with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. 24-h IFN-α or IFN-□ treatment induced a two-fold increase in EV PD-L1 cargo without a corresponding increase in number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8 T cells. Plasma EV PD-L1 levels were increased in islet Ab+ individuals, particularly in those with single Ab+, Additionally, in from individuals with either Ab+ or type 1 diabetes, but not in controls, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV-PD-L1 could be protective for residual beta cell function. Conclusions/interpretation: IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8 T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in islet autoantibody positive patients compared to controls. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death. Research in context: What is already known about this subject? (maximum of 3 bullet points): Extracellular vesicles (EVs) serve as paracrine effectors in the islet microenvironment in health and disease.Interferon-alpha (IFN-α) and IFN-gamma (IFN-□) are key cytokines contributing to type 1 diabetes pathophysiology and islet IFN signalling increases beta cell programmed death-ligand 1 (PD-L1) expression.Up-regulation of beta cell PD-L1 in the non-obese diabetic (NOD) mouse model delays progression of type 1 diabetes.What is the key question? (one bullet point only; formatted as a question): Do beta cells exposed to IFNs upregulate EV PD-L1 and can these changes be detected in circulation?What are the new findings? (maximum of 3 bullet points): IFN-α or IFN-□ exposure increases beta cell EV PD-L1 cargo in beta cell lines and human islets.PD-L1 is present on the surface of beta cell EVs, binds PD-1 and EV PD-L1 inhibits proliferation, activation and cytotoxicity of murine CD8 T cells.EV PD-L1 levels are higher in islet autoantibody positive individuals compared to nondiabetic controls and levels of circulating EV PD-L1 positively correlate with residual beta cell function in islet autoantibody positive individuals as well as in individuals with recent-onset type 1 diabetes.How might this impact on clinical practice in the foreseeable future? (one bullet point only): A beneficial effect of PD-L1+ EVs could ultimately be harnessed as an intervention to prevent autoimmune beta cell destruction. Circulating EV PD-L1 cargo has potential as a minimally invasive and informative biomarker to offer insights into the pathogenesis and progression of type 1 diabetes.

Large-Scale Screening of Per- and Polyfluoroalkyl Substance Binding Interactions and Their Mixtures with Nuclear Receptors.

Despite their significant impact, comprehensive screenings and detailed analyses of per- and polyfluoroalkyl substance (PFAS) binding strengths at the orthosteric and allosteric sites of NRs are currently lacking. This study addresses this gap by focusing on the binding interaction analysis of both common and uncommon PFAS with the nuclear receptors (NRs) vitamin D receptor (VDR), peroxisome proliferator-activated receptor gamma (PPARγ), pregnane X receptor (PXR), and estrogen receptor alpha (ERα). Advanced docking simulations were used to screen 9507 PFAS chemicals at the orthosteric and allosteric sites of PPARγ, PXR, VDR, and ERα. All receptors exhibited strong binding interactions at the orthosteric and allosteric site with a significant number of PFAS. We verified the accuracy of the docking protocol through multiple docking controls and validations. A mixture modeling analysis indicates that PFAS can bind in various combinations with themselves and endogenous ligands simultaneously, to disrupt the endocrine system and cause carcinogenic responses. These findings reveal that PFAS can interfere with nuclear receptor activity by displacing endogenous or native ligands by binding to the orthosteric and allosteric sites. The purpose of this study is to explore the mechanisms through which PFAS exert their endocrine-disrupting effects, potentially leading to more targeted therapeutic strategies. Importantly, this study is the first to explore the binding of PFAS at allosteric sites and to model PFAS mixtures at nuclear receptors. Given the high concentration and persistence of PFAS in humans, this study further emphasizes the urgent need for further research into the carcinogenic mechanisms of PFAS and the development of therapeutic strategies that target nuclear receptors.

Ultrasmall copper-metal organic framework (Cu-MOF) quantum dots decorated on waste derived biochar for enhanced removal of emerging contaminants: Synergistic effect and mechanistic insight.

This study proposes a novel one-pot hydrothermal impregnation strategy for surface decoration of waste derived pisum sativum biochar with zero‒dimensional Cu‒MOF Quantum dots (PBC‒HK), with an average particle size of 5.67 nm, for synergistic removal of an emerging sulfur containing drug pantoprazole (PTZ) and Basic Blue 26 (VB) dye within 80 min and 50 min of visible-light exposure, respectively. The designed Integrated Photocatalytic Adsorbent (IPA) presented an enhanced PTZ removal efficiency of 95.23% with a catalyst loading of 0.24 g/L and initial PTZ conc. 30 mg/L at pH 7, within 80 min via synergistic adsorption and photodegradation under visible-light exposure. While, on the other hand, 96.31% VB removal efficiency was obtained in 50 min with a catalyst dosage of 0.20 g/L, initial VB conc. 60 mg/L at pH 7 under similar irradiation conditions. An in-depth analysis of the synergistic adsorption and photocatalysis mechanism resulting in the shortened time for the removal of contaminants in the synergistic integrated model has been performed by outlining the various advantageous attributes of this strategy. The first-order degradation rate constant for PTZ was found to be 0.04846 min-1 and 0.04370 min-1 for PTZ and VB, respectively. Adsorption of contaminant molecules on the biochar (PS‒BC) surface can facilitate photodegradation by accelerating the kinetics, and photodegradation promotes regeneration of adsorption sites, contributing to an overall reduction in operation time for removal of contaminants. Besides enhancing the adsorption of targeted pollutants, the carbon matrix of IPAs serves as a surface for adsorption of intermediates of degradation, thereby minimizing the risk of secondary pollution. The photogenerated holes present in the VB is responsible for the generation of •OH radicals. While, the photogenerated electrons present in the CB are captured by Cu2+ of the MOF metal center, reducing it to Cu+, which is subsequently oxidized to produce additional •OH species in the aqueous medium. This process leads to effective charge separation of the photogenerated charge carriers and minimizes the probability of charge recombination as evident from photoluminescence (PL) analysis. Meanwhile, PL studies, EPR and radical trapping experiments indicate the predominant role of •OH radicals in the removal mechanism of PTZ and VB. The investigation of the degradation reaction intermediates was confirmed by HR‒LCMS, on the basis of which the plausible degradation pathway was elucidated in detail. Moreover, effects of pH, inorganic salts, other organic compounds and humic acid concentration have been investigated in detail. The environmental impact of the proposed method was comprehensively evaluated by ICP-OES analysis and TOC and COD removal studies. Furthermore, the economic feasibility and the cost-effectiveness of the catalyst was assessed to address the potential for large scale commercialization. Notably, this research not only demonstrates a rational design strategy for the utilization of solid waste into treasure via the fabrication of IPAs based on MOF Quantum dots (QDs) and waste-derived biochar, but also provides a practical solution for real wastewater treatment systems for broader industrial applications.

Decoding the immune dance: Unraveling the interplay between beta cells and type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by the specific destruction of insulin-producing beta cells in the pancreas by the immune system, including CD4 cells which orchestrate the attack and CD8 cells which directly destroy the beta cells, resulting in the loss of glucose homeostasis. SCOPE OF REVIEW: This comprehensive document delves into the complex interplay between the immune system and beta cells, aiming to shed light on the mechanisms driving their destruction in T1D. Insights into the genetic predisposition, environmental triggers, and autoimmune responses provide a foundation for understanding the autoimmune attack on beta cells. From the role of viral infections as potential triggers to the inflammatory response of beta cells, an intricate puzzle starts to unfold. This exploration highlights the importance of beta cells in breaking immune tolerance and the factors contributing to their targeted destruction. Furthermore, it examines the potential role of autophagy and the impact of cytokine signaling on beta cell function and survival. MAJOR CONCLUSIONS: This review collectively represents current research findings on T1D which offers valuable perspectives on novel therapeutic approaches for preserving beta cell mass, restoring immune tolerance, and ultimately preventing or halting the progression of T1D. By unraveling the complex dynamics between the immune system and beta cells, we inch closer to a comprehensive understanding of T1D pathogenesis, paving the way for more effective treatments and ultimately a cure.

ZnO-based Cu metal-organic framework (MOF) nanocomposite for boosting and tuning the photocatalytic degradation performance.

Although metal-organic frameworks (MOFs) are a viable choice for photocatalysts with large surface area and tunable pore structure, the rapid recombination of excited photogenerated charges results in low activity towards photodegradation. Aiming at improving the photocatalytic activities of MOFs, different strategies to incorporate MOF with light-harvesting semiconductors have been developed. In this research, we report an effective photocatalyst designed by incorporating Cu-MOF with ZnO for the photocatalytic degradation of Rose Bengal exhibiting excellent degradation efficiency of 97.4% in 45 min under natural sunlight with catalyst dosage of 320 mg/L. The optical, morphology and surface characteristics of the prepared nanocomposite were studied using scanning electron microscopy (SEM-EDX), high-resolution transmission electron microscopy (HRTEM), powder X-ray diffraction (PXRD), Brunauer-Emmett-Teller (BET) analysis, thermogravimetric (TGA) analysis, Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and ultraviolet diffused reflectance spectroscopy (UV-DRS) techniques. Further studies showed that the degradation followed first-order kinetics with a rate constant of 0.077869 min-1. The degradation mechanism was investigated by photoluminescence (PL) study, XPS, zeta potential and quenching experiment in presence of different scavengers. Meanwhile, the fabricated composite displayed good recovery and reuse properties up to 5 cycles as revealed by XRD analysis proving itself a potential MOF-based photocatalyst towards environmental remediation process.

Sustainable degradation of pollutants, generation of electricity and hydrogen evolution via photocatalytic fuel cells: An Inclusive Review.

Environmental pollution and energy crisis have recently become one of the major global concerns. Insincere discharge of massive amount of organic and inorganic wastes into the aqueous bodies causes serious impact on our environment. However, these organic substances are significant sources of carbon and energy that could be sustainably utilized rather than being discarded. Photocatalytic fuel cell (PFC) is a smart and novel energy conversion device that has the ability to achieve dual benefits: degrading the organic contaminants and simultaneously generating electricity, thereby helping in environmental remediation. This article presents a detailed study of the recent advancements in the development of PFC systems and focuses on the fundamental working principles of PFCs. The degradation of various common organic and inorganic contaminants including dyes and antibiotics with simultaneous power generation and hydrogen evolution has been outlined. The impact of various operational factors on the PFC activity has also been briefly discussed. Moreover, it provides an overview of the design guidelines of the different PFC systems that has been developed recently. It also includes a mention of the materials employed for the construction of the photo electrodes and highlights the major limitations and relevant research scopes that are anticipated to be of interest in the days to come. The review is intended to serve as a handy resource for researchers and budding scientists opting to work in this area of PFC devices.

Resilience and its correlates among medical students in the Eastern part of India during the coronavirus disease 2019 (COVID-19) pandemic.

BACKGROUND: There is a great deal of psychological pressure on medical students, which results in depression, addiction, and suicide. Resilience plays a significant role in coping with psychological distress. The study aimed to determine the resilience level of medical students in Kolkata and factors related to it. MATERIALS AND METHODS: A cross-sectional study was conducted among undergraduate students of a medical college in the eastern part of India during October 2020. Resilience was assessed using the validated "Adult Resilience Measure-R." Data were collected on Google Forms and analyzed using SPSS (version 16.0). Logistic regression analysis was performed to find factors associated with low resilience. RESULTS: The study revealed that one-fourth (25.2%) of the participants had low-level resilience. Nearly half (44.9%) of them perceived their mental health status as having worsened during the lockdown. Students who did not enjoy staying at home during the lockdown and who spent <10 h of their time with their family members had higher odds of low resilience. In multivariable analysis, not enjoying staying at home during the lockdown remained the only significant predictor of low resilience. CONCLUSION: Students should spend more time with their parents and family members and learn coping skills. Appropriate resilience training programs have to be integrated into the medical curriculum to help in coping with future challenges.

Role of MrgprB2 in Rosacea-Like Inflammation in Mice: Modulation by ß-Arrestin 2.

Cathelicidin LL-37‒mediated activation of mast cells (MCs) has been implicated in the pathogenesis of rosacea, but the receptor involved and the mechanism of its activation and regulation remain unknown. We found that skin biopsies from patients with rosacea display higher frequencies of MCs expressing MRGPRX2 (mouse counterpart MrgprB2) than normal skin. Intradermal injection of LL-37 in wild-type mice resulted in MC recruitment, expression of inflammatory mediators, and development of rosacea-like inflammation. These responses were substantially reduced in MrgprB2‒/‒ mice and abolished in MC deficient Wsh/Wsh mice. ß-arrestin 2 is an adaptor protein that regulates G protein-coupled receptor function by receptor desensitization and also by activation of downstream signaling. We found that LL-37‒induced rosacea-like inflammation was significantly reduced in mice with MC-specific deletion of ß-arrestin 2 compared with that in control mice. Interestingly, the absence of ß-arrestin 2 resulted in enhanced cofilin phosphorylation and substantial inhibition of LL-37‒induced chemotaxis of mouse peritoneal MCs. Furthermore, LL-37‒induced extracellular signal‒regulated kinase 1/2 phosphorylation, NF-κB activation, and proinflammatory cytokine/chemokine production were reduced in ß-arrestin 2‒/‒ peritoneal MCs compared with those in wild-type cells. These findings suggest that MRGPRX2/B2 participates in rosacea and that ß-arrestin 2 contributes to its pathogenesis by promoting cofilin dephosphorylation, extracellular signal‒regulated kinase 1/2 and NF-κB phosphorylation, MC chemotaxis, and chemokine/cytokine generation.

Ionic liquid based composites: A versatile materials for remediation of aqueous environmental contaminants.

Water pollution is one of the most aggravated problems threatening the sustainability of human race and other life forms due to the rapid pace of civilization and industrialization. A long history exists of release of hazardous pollutants into the water bodies due to selfish human activities since the Industrial Revolution, but no effort has been completely successful in curbing the activities that result in the degradation of our environment. These pollutants are harmful, carcinogenic and have adverse health effects to all forms of life. Thus, remarkable efforts have been geared up to obtain clean water by exploiting science and technology. The application of Ionic liquids (ILs) as sustainable materials have received widespread attention since the last decade. Their interesting properties, simplicity in operation and satisfactory binding capacities in elimination of the contaminants makes them a valuable prospect to be utilized in wastewater treatment. Immobilizing and grafting the solid supports with ILs have fetched efficient results to exploit their potential in the adsorptive removal processes. This review provides an understanding of the recent developments and outlines the possible utility of IL based nano adsorbents in the removal of organic compounds, dyes and heavy metal ions from aqueous medium. Effect of several parameters such as sorbent dosage, pH and temperature on the removal efficiency has also been discussed. Moreover, the adsorption isotherms, thermodynamics and mechanism are comprehensively studied. It is envisioned that the literature gathered in this article will guide the budding scientists to put their interest in this area of research in the days to come.

DOCK2 Promotes Pleural Fibrosis by Modulating Mesothelial to Mesenchymal Transition.

Mesothelial to mesenchymal transition (MesoMT) is one of the crucial mechanisms underlying pleural fibrosis, which results in restrictive lung disease. DOCK2 (dedicator of cytokinesis 2) plays important roles in immune functions; however, its role in pleural fibrosis, particularly MesoMT, remains unknown. We found that amounts of DOCK2 and the MesoMT marker α-SMA (α-smooth muscle actin) were significantly elevated and colocalized in the thickened pleura of patients with nonspecific pleuritis, suggesting the involvement of DOCK2 in the pathogenesis of MesoMT and pleural fibrosis. Likewise, data from three different pleural fibrosis models (TGF-ß [transforming growth factor-ß], carbon black/bleomycin, and streptococcal empyema) consistently demonstrated DOCK2 upregulation and its colocalization with α-SMA in the pleura. In addition, induced DOCK2 colocalized with the mesothelial marker calretinin, implicating DOCK2 in the regulation of MesoMT. Our in vivo data also showed that DOCK2-knockout mice were protected from Streptococcus pneumoniae-induced pleural fibrosis, impaired lung compliance, and collagen deposition. To determine the involvement of DOCK2 in MesoMT, we treated primary human pleural mesothelial cells with the potent MesoMT inducer TGF-ß. TGF-ß significantly induced DOCK2 expression in a time-dependent manner, together with α-SMA, collagen 1, and fibronectin. Furthermore, DOCK2 knockdown significantly attenuated TGF-ß-induced α-SMA, collagen 1, and fibronectin expression, suggesting the importance of DOCK2 in TGF-ß-induced MesoMT. DOCK2 knockdown also inhibited TGF-ß-induced Snail upregulation, which may account for its role in regulating MesoMT. Taken together, the current study provides evidence that DOCK2 contributes to the pathogenesis of pleural fibrosis by mediating MesoMT and deposition of neomatrix and may represent a novel target for its prevention or treatment.