Search

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFN-γ and anti-TNF-α prevented CPI-DM in anti-PD-L1-treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.

SIGNIFICANCE:Various autoimmune syndromes are characterized by abnormalities found at the level of tissues and cells, as well as by microenvironmental influences, such as reactive oxygen species (ROS), that alter intracellular metabolism and protein expression. Moreover, the convergence of genetic, epigenetic, and even environmental influences can result in B and T lymphocyte autoimmunity and tissue pathology. Recent Advances: This review describes how oxidative stress to cells and tissues may alter post-translational protein modifications, both directly and indirectly, as well as potentially lead to aberrant gene expression. For example, it has been clearly observed in many systems how oxidative stress directly amplifies carbonyl protein modifications. However, ROS also lead to a number of nonenzymatic spontaneous modifications including deamidation and isoaspartate modification as well as to enzyme-mediated citrullination of self-proteins. ROS have direct effects on DNA methylation, leading to influences in gene expression, chromosome inactivation, and the silencing of genetic elements. Finally, ROS can alter many other cellular pathways, including the initiation of apoptosis and NETosis, triggering the release of modified intracellular autoantigens. CRITICAL ISSUES:This review will detail specific post-translational protein modifications, the pathways that control autoimmunity to modified self-proteins, and how products of ROS may be important biomarkers of tissue pathogenesis. FUTURE DIRECTIONS:A clear understanding of the many pathways affected by ROS will lead to potential therapeutic manipulations to alter the onset and/or progression of autoimmune disease.

Objective/Background: Taxodium distichum (L.) Rich., a plant of the Cupressaceae family, is known for its leaves and cones rich in essential oils, which are traditionally used in folk medicine. This study employed hydrodistillation to extract essential oils from three parts of T. distichum, namely its leaves, twigs, and cones, and evaluated the yield and composition of these oils as well as their anti-mildew property on paper. Methods: The chemical compositions of the essential oils from the three parts were analyzed using gas chromatography with flame ionization detection (GC-FID) and gas chromatography mass spectrometry (GC-MS). The anti-mildew properties were assessed on paper against seven mold fungi, namely Aspergillus clavatus, A. niger, Chaetomium globosum, Cladosporium cladosporioides, Myrothecium verrucaria, Penicillium citrinum, and Trichoderma viride, following standards such as TAPPI T487 cm-93 and CNS 2690. Furthermore, the essential oil demonstrating the strongest anti-mildew properties was selected from the oils extracted from three different parts, underwent column chromatography for isolation, and the main active compounds were identified. Results: Among the three parts, cones had the highest essential oil yield (0.53 ± 0.03 mL/100 g), followed by leaves (0.46 ± 0.02 mL/100 g) and twigs (0.06 ± 0.01 mL/100 g). The main components were limonene (39.8%) and α-pinene (37.1%) in leaves; limonene (16.8%), α-pinene (15.8%), and ferruginol (11.0%) in twigs; and ferruginol (43.2%) and caryophyllene oxide (12.5%) in cones. The cone oils exhibited the most effective anti-mildew properties on paper. Furthermore, the cone oils were fractionated into six fractions (CO1–CO6), with the CO4 fraction exhibiting the best activity. CO4's main components were ferruginol, caryophyllene oxide, and β-caryophyllene. Ferruginol showed the best anti-mildew performance, with 100% inhibition at 200 μg/cm² for all strains. Conclusion: The study results indicated that essential oils from the cones of T. distichum and ferruginol exhibit promising anti-mildew effects on paper. Therefore, further research and development are highly warranted for their application in inhibiting fungal growth on paper. [ABSTRACT FROM AUTHOR]

Augmented reality (AR) offers potential advantages for intensifying environmental context awareness and augmenting students' experiences in real-world environments by dynamically overlapping digital materials with a real-world environment. However, some challenges to AR learning environments have been described, such as participants' cognitive overload and the ways to provide assistance in constructing the presented learning materials. In this study, a mindtool-based AR learning system was developed, based on the repertory grid method and the contiguity principle of multimedia learning, for assisting students in constructing their knowledge in a natural science course. Furthermore, an experiment was carried out on an elementary school natural science course to compare the influences of this method with those of the conventional AR learning system on students' learning effectiveness. The experimental results show that the designated approach effectively promoted the students' learning achievements, and no significant difference existed between the mindtool-based AR learning system and the conventional AR learning system in terms of students' cognition load and satisfaction degree; moreover, both the experimental group and the control group perceived low cognition load during the learning activity and rated their own AR learning systems as being highly satisfactory.

Metal element contents in water samples are commonly determined by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). ICP-MS has a low detection limit and wide linear range, but has a high power, large gas consumption, and high cost. A rapid method for the determination of calcium ions in water samples was developed by using Microwave Plasma Torch (MPT)-Mass Spectrometry coupled with pneumatic nebulization. The effects of carrier gas flow rate and the support gas flow rate on calcium response signal were investigated. The detection limit of this method is 224.56 ng/L, relative standard deviations (RSDs) are 1.2%-9.8%, and recoveries range from 86.3% to 110.4%. This method avoids sample pretreatment, and has a short analysis time, good sensitivity and precision. This method provides a new approach for the determination of metal ions in environmental water and may be used for in situ analysis in the future.

The distinction between natural stones such as marble and granite, and artificial stones formed mostly by unsaturated polyester resin with the addition of disintegrating slag of natural stone and some additives is difficult to determine accurately and quickly by chemical composition. Consequently, the development of Infrared Reflection Spectroscopy (IRS) has been established for for this purpose, but has limitations due to the high purity requirement of samples. Based on the high ability of thermal desorption and ionization of Microwave Plasma Torch (MPT), analyte could be ionized in a short time. In this study, Microwave Plasma Torch Mass Spectrometry (MPT-MS) was used to directly analyze natural and artificial stone without sample pretreatment. The fingerprint mass spectra of these stones were obtained in the mass range of m/z 50-1000. All data from artificial stones and natural stones were analyzed by principal component analysis (PCA) for differentiation of artificial and natural stones. The results show that abundant fingerprints of stones were acquired by MPT-MS. With the application of PCA, natural stones were successfully and rapidly differentiated from artificial stones. CO2 and H2O molecular clusters were desorbed from natural stones, however, organics (i.e. adhesives) were desorbed from artificial stone. Herein, MPT-MS is a new mass spectrometry technology under atmospheric pressure. Without the assistance of spray, laser, matrix and heat, the stones can be analyzed by MPT-MS directly. The method has high analytical speed (1 min per sample), high sensitivity, and does not require sample pretreatment. The results indicate that direct MPT-MS analysis allows rapid differentiation of untreated solid materials, such as construction stones, at the molecular level.

This study examined the chemical composition and antimicrobial activities of essential oils isolated from the leaves, twigs, and fruits of Neolitsea sericea var. aurata from Taiwan. The major compounds responsible for antimicrobial activity were isolated and identified. The leaf, twig, and fruit essential oils were obtained through hydrodistillation in a Clevenger-type apparatus and were characterized through gas chromatography (GC) with flame ionization detection (GC/FID) and GC/mass spectrometry (GC/MS). The major compounds were (E)-β-ocimene (49.3%) and sericenine (31.6%) in the leaf oil; (E)-β-ocimene (73.7%), α-cadinol (6.8%), and α-muurolol (4.0%) in the twig oil; and (E)-β-ocimene (84.7%) in the fruit oil. The twig oil exhibited the strongest antibacterial and antifungal activities. We isolated α-cadinol and α-muurolol, the main components of NTO4 fraction, and used them in antimicrobial tests; the two compounds exhibited excellent antimicrobial activities. The twig essential oil contains α-cadinol and α-muurolol and exhibited excellent antimicrobial activities against food-borne pathogens; thus, they are worthy of further research and development. [ABSTRACT FROM AUTHOR]