Effects of Hydrogen Inhalation on Neurological Function Indicators, Oxidative Stress Markers, and E-Cadherin Levels in Patients with Brain Glioma.

Objective: This study aims to evaluate the effects of hydrogen therapy on nerve function and tumor progression markers in glioma patients, focusing on the modulation of oxidative stress and cadherin expression to establish its potential as a complementary treatment. Methods: 100 glioma patients were enrolled and divided into two groups using the random number table: routine treatment (50) and hydrogen inhalation plus routine treatment (50). After 2 weeks of treatment, clinical curative effect, levels of nerve function indexes [national institute of health stroke scale (NIHSS), central nervous specific protein (S100ß), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP)], oxidative stress indexes [malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT)] and E-cadherin before and after treatment, and occurrence of adverse reactions during treatment were compared between the two groups. Results: After treatment, the overall effect of the hydrogen inhalation group (90.00%) was significantly better than that of the conventional group (72.00%), which was statistically significant (P = .022). In terms of specific biomarkers, post-treatment levels of E-cadherin were elevated to 0.84±0.05 ng/mL in the hydrogen group compared to 0.72±0.06 ng/mL in the routine group. SOD and CAT levels rose to 63.21±5.36 U/L and 8.01±0.54 U/mL, respectively, versus 52.31±5.24 U/L and 5.25±0.59 U/mL in the routine group (P < .05 for both). Conversely, the NIHSS scores decreased significantly to 12.19±2.08 in the hydrogen group, compared to 16.92±2.23 in the routine group. Similarly, S100ß, NSE, GFAP, and MDA levels were found to be lower in the hydrogen group (0.41±0.09 µg/L, 8.24±1.64 ng/mL, 0.71±0.23 pg/mL, and 6.05±1.08 mmol/L respectively) than in the routine group (0.66±0.12 µg/L, 10.67±1.83 ng/mL, 0.93±0.29 pg/mL, and 7.21±1.12 mmol/L respectively) with P < .05 for all comparisons. The total incidence of adverse reactions was slightly lower in the hydrogen group (64.00%) compared to the routine group (68.00%), but this difference was not statistically significant (χ2=0.178, P = .673). Conclusion: Hydrogen inhalation therapy significantly enhances nerve function, reduces local oxidative stress levels, and increases E-cadherin levels in patients with brain glioma, suggesting its potential as an adjunct treatment. The findings underscore the therapy's role in enhancing patient recovery and guiding future research and treatment strategies.

Tfh cell-derived small extracellular vesicles exacerbate the severity of collagen-induced arthritis by enhancing B-cell responses.

Soluble components secreted by Tfh cells are critical for the germinal center responses. In this study, we investigated whether Tfh cells could regulate the B-cell response by releasing small extracellular vesicles (sEVs). Our results showed that Tfh cells promote B-cell differentiation and antibody production through sEVs and that CD40L plays a crucial role in Tfh-sEVs function. In addition, increased Tfh-sEVs were found in mice with collagen-induced arthritis (CIA). Adoptive transfer of Tfh cells significantly exacerbated the severity of CIA; however, the effect of Tfh cells on exacerbating the CIA process was significantly diminished after inhibiting sEVs secretion. Moreover, the levels of plasma Tfh-like-sEVs and CD40L expression on Tfh-like-sEVs in RA patients were significantly higher than those in healthy subjects. In summary, Tfh cell-derived sEVs can enhance the B-cell response, and exacerbate the procession of autoimmune arthritis.

Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.

The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.

The role of TET2 in solid tumors and its therapeutic potential: a comprehensive review.

Indeed, tumors are a significant health concern worldwide, and understanding the underlying mechanisms of tumor development is crucial for effective prevention and treatment. Epigenetics, which refers to changes in gene expression that are not caused by alterations in the DNA sequence itself, plays a critical role in the entire process of tumor development. It goes without saying that the effect of methylation on tumors is a significant aspect of epigenetics. Among the methylation modifications, DNA methylation is an important part, which plays a regulatory role in tumor-related genes. Ten-eleven translocation 2 (TET2) is a highly influential protein involved in the modification of DNA methylation. Its primary role is associated with the suppression of tumor development, making it a significant player in cancer research. However, TET2 is frequently mentioned in hematological diseases, its role in solid tumors has received little attention. Studying the changes of TET2 in solid tumors and the regulatory mechanism will facilitate its investigation as a clinical target for targeted therapy and may also provide directions for clinical treatment of malignant tumors.

The Role of Citrullination Modification in CD4+ T Cells in the Pathogenesis of Immune-Related Diseases.

The post-translational modifications (PTMs) of proteins play a crucial role in increasing the functional diversity of proteins and are associated with the pathogenesis of various diseases. This review focuses on a less explored PTM called citrullination, which involves the conversion of arginine to citrulline. This process is catalyzed by peptidyl arginine deiminases (PADs). Different members of the PAD family have distinct tissue distribution patterns and functions. Citrullination is a post-translational modification of native proteins that can alter their structure and convert them into autoantigens; thus, it mediates the occurrence of autoimmune diseases. CD4+ T cells, including Th1, Th2, and Th17 cells, are important immune cells involved in mediating autoimmune diseases, allergic reactions, and tumor immunity. PADs can induce citrullination in CD4+ T cells, suggesting a role for citrullination in CD4+ T cell subset differentiation and function. Understanding the role of citrullination in CD4+ T cells may provide insights into immune-related diseases and inflammatory processes.

ALKBH5 regulates arginase 1 expression in MDSCs and their immunosuppressive activity in tumor-bearing host.

Myeloid-derived suppressor cells (MDSCs) are closely related to the occurrence and development of many cancers, but the specific mechanism is not fully understood. It has been found that N6-methyladenosine (m6A) plays a key role in RNA metabolism, but its function in MDSCs has yet to be revealed. In this study, we found that MDSCs in mice with colorectal cancer (CRC) have significantly elevated levels of m6A, while ALKBH5 expression is decreased. Overexpression of ALKBH5 can reduce the immunosuppressive function of MDSCs in vivo and in vitro, and attenuates the protumorigenic ability of MDSCs. Mechanism study found that the overexpression of ALKBH5 in MDSCs reduced the m6A modification level of Arg-1 mRNA, and then weakened the stability of Arg-1 mRNA and protein expression. These data suggest that the decreased expression of ALKBH5 in CRC tumor mice may promote the expression of Arg-1, enhance the immunosuppressor function of MDSCs, and promote tumor growth. These findings highlight that ALKBH5 may regulate the function of MDSCs in tumor-bearing mice and may be a new target for immunotherapy. This research provides a new perspective for our understanding of the role of MDSCs in cancer development, and also brings new hope for cancer treatment.

Rapamycin alleviates mitochondrial dysfunction in anti-NMDAR encephalitis mice.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most prevalent forms of autoimmune encephalitis, characterized by a series of neurological and psychiatric symptoms, including cognitive impairment, seizures and psychosis. The underlying mechanism of anti-NMDAR encephalitis remains unclear. In the current study, the mouse model of anti-NMDAR encephalitis with active immunization was performed. We first uncovered excessive mitochondrial fission in the hippocampus and temporal cortex of anti-NMDAR encephalitis mice, indicated by elevated level of Phospho-DRP1 (Ser616) (p-Drp1-S616). Moreover, blockade of the autophagic flux was also demonstrated, leading to the accumulation of fragmented mitochondria, and elevated levels of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) in anti-NMDAR encephalitis. More importantly, we found that the mTOR signaling pathway was overactivated, which could aggravate mitochondrial fission and inhibit autophagy, resulting in mitochondrial dysfunction. While rapamycin, the specific inhibitor of the mTOR signaling pathway, significantly alleviated mitochondrial dysfunction by inhibiting mitochondrial fission and enhancing autophagy. Levels of mtROS and mtDNA were markedly reduced after the treatment of rapamycin. In addition, rapamycin also significantly alleviated cognitive dysfunction and anxious behaviors found in anti-NMDAR encephalitis mice. Thus, our study reveals the vital role of mitochondrial dysfunction in pathological mechanism of anti-NMDAR encephalitis and lays a theoretical foundation for rapamycin to become a clinically targeted drug for anti-NMDAR encephalitis.

Correction: Enhancing Specific-Antibody Production to the ragB Vaccine with GITRL That Expand Tfh, IFN-γ+ T Cells and Attenuates Porphyromonas gingivalis Infection in Mice.

[This corrects the article DOI: 10.1371/journal.pone.0059604.].

Predicting nonsmooth chaotic dynamics by reservoir computing.

Reservoir computing (RC) has been widely applied to predict the chaotic dynamics in many systems. Yet much broader areas related to nonsmooth dynamics have seldom been touched by the RC community which have great theoretical and practical importance. The generalization of RC to this kind of system is reported in this paper. The numerical work shows that the conventional RC with a hyperbolic tangent activation function is not able to predict the dynamics of nonsmooth systems very well, especially when reconstructing attractors (long-term prediction). A nonsmooth activation function with a piecewise nature is proposed. A kind of physics-informed RC scheme is established based on this activation function. The feasibility of this scheme has been proven by its successful application to the predictions of the short- and long-term (reconstructing chaotic attractor) dynamics of four nonsmooth systems with different complexity, including the tent map, piecewise linear map with a gap, both noninvertible and discontinuous compound circle maps, and Lozi map. The results show that RC with the new activation function is efficient and easy to run. It can make perfectly both short- and long-term predictions. The precision of reconstructing attractors depends on their complexity. This work reveals that, to make efficient predictions, the activation function of an RC approach should match the smooth or nonsmooth nature of the dynamical systems.

Ubiquitination and deubiquitination in the regulation of N6-methyladenosine functional molecules.

N6 methyladenosine (m6A) is the most prevalent RNA epigenetic modification, regulated by methyltransferases and demethyltransferases and recognized by methylation-related reading proteins to impact mRNA splicing, translocation, stability, and translation efficiency. It significantly affects a variety of activities, including stem cell maintenance and differentiation, tumor formation, immune regulation, and metabolic disorders. Ubiquitination refers to the specific modification of target proteins by ubiquitin molecule in response to a series of enzymes. E3 ligases connect ubiquitin to target proteins and usually lead to protein degradation. On the contrary, deubiquitination induced by deubiquitinating enzymes (DUBs) can separate ubiquitin and regulate the stability of protein. Recent studies have emphasized the potential importance of ubiquitination and deubiquitination in controlling the function of m6A modification. In this review, we discuss the impact of ubiquitination and deubiquitination on m6A functional molecules in diseases, such as metabolism, cellular stress, and tumor growth.

Tandem phospha-Michael addition/cyclization/dehydration of 2-hydroxychalcones with H-phosphine oxides for the synthesis of 4-phosphorylated 4H-chromenes.

A Hg(OTf)2-catalyzed tandem phospha-Michael addition/cyclization/dehydration of 2-hydroxychalcones with H-phosphine oxides is presented. This protocol provides a new and supplementary approach for the preparation of 4-phosphorylated 4H-chromenes in good yields (up to 99%). In addition, this domino reaction allows the successful construction of two new C-P and C-O bonds in a one-pot operation.

Multilevel and multifaceted brain response features in spiking, ERP and ERD: experimental observation and simultaneous generation in a neuronal network model with excitation-inhibition balance.

Brain as a dynamic system responds to stimulations with specific patterns affected by its inherent ongoing dynamics. The patterns are manifested across different levels of organization-from spiking activity of neurons to collective oscillations in local field potential (LFP) and electroencephalogram (EEG). The multilevel and multifaceted response activities show patterns seemingly distinct and non-comparable from each other, but they should be coherently related because they are generated from the same underlying neural dynamic system. A coherent understanding of the interrelationships between different levels/aspects of activity features is important for understanding the complex brain functions. Here, based on analysis of data from human EEG, monkey LFP and neuronal spiking, we demonstrated that the brain response activities from different levels of neural system are highly coherent: the external stimulus simultaneously generated event-related potentials, event-related desynchronization, and variation in neuronal spiking activities that precisely match with each other in the temporal unfolding. Based on a biologically plausible but generic network of conductance-based integrate-and-fire excitatory and inhibitory neurons with dense connections, we showed that the multiple key features can be simultaneously produced at critical dynamical regimes supported by excitation-inhibition (E-I) balance. The elucidation of the inherent coherency of various neural response activities and demonstration of a simple dynamical neural circuit system having the ability to simultaneously produce multiple features suggest the plausibility of understanding high-level brain function and cognition from elementary and generic neuronal dynamics. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09889-w.

Rotating Lorentz Force Magnetic Bearings' Dynamics Modeling and Adaptive Controller Design.

To address the issues of our agile satellites' poor attitude maneuverability, low pointing stability, and pointing inaccuracy, this paper proposes a new type of stabilized platform based on seven-degree-of-freedom Lorentz force magnetic levitation. Furthermore, in this study, we designed an adaptive controller based on the RBF neural network for the rotating magnetic bearing, which can improve the pointing accuracy of satellite loads. To begin, the advanced features of the new platform are described in comparison with the traditional electromechanical platform, and the structural characteristics and working principle of the platform are clarified. The significance of rotating magnetic bearings in improving load pointing accuracy is also clarified, and its rotor dynamics model is established to provide the input and output equations. The adaptive controller based on the RBF neural network is designed for the needs of high accuracy of the load pointing, high stability, and strong robustness of the system, and the current feedback inner loop is added to improve the system stiffness and rapidity. The final simulation results show that, when compared to the PID controller and robust sliding mode controller, the controller's pointing accuracy and anti-interference ability are greatly improved, and the system robustness is strong, which can effectively improve the pointing accuracy and pointing stability of the satellite/payload, as well as provide a powerful means of solving related problems in the fields of laser communication, high score detection, and so on.

Targeting STING in cancer: Challenges and emerging opportunities.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a key pathway through which the host regulates immune responses by recognizing cytoplasmic double-stranded DNA of abnormal origin, and it plays an important role in tumor growth as well as metastasis, with relevant molecular details constantly being explored and updated. The significant immunomodulatory effects make STING an attractive target for cancer immunotherapy, and STING agonists have been receiving great attention for their development and clinical translation. Despite exciting results in preclinical work, the application of STING agonists to cancer therapy remains challenging due to their poor pharmacokinetic and physicochemical properties, as well as toxic side effects they produce. Here, we summarize the dichotomous role of cGAS-STING in cancer and discuss the limitations of cancer immunotherapy based on STING activation as well as feasible strategies to overcome them to achieve tumor regression.

Tumor microenvironment, histone modifications, and myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are important components of the tumor microenvironment (TME), which drive the tumor immune escape by inducing immunosuppression. The expansion and function of MDSCs are tightly associated with signaling pathways induced by molecules from tumor cells, stromal cells, and activated immune cells in the TME. Although these pathways have been well-characterized, the understanding of the epigenetic regulators involved is incomplete. Since histone modifications are the most studied epigenetic changes in MDSCs, we summarize current knowledge on the role of histone modifications in MDSCs within this review. We first discuss the influence of the TME on histone modifications in MDSCs, with an emphasis on histone modifications and modifiers that direct MDSC differentiation and function. Furthermore, we highlight current epigenetic interventions that can reverse MDSC-induced immunosuppression by modulating histone modifications and discuss future research directions to fully appreciate the role of histone modifications in MDSCs.

Function of reactive oxygen species in myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous myeloid cell population and serve as a vital contributor to the tumor microenvironment. Reactive oxygen species (ROS) are byproducts of aerobic respiration and are involved in regulating normal biological activities and disease progression. MDSCs can produce ROS to fulfill their immunosuppressive activity and eliminate excessive ROS to survive comfily through the redox system. This review focuses on how MDSCs survive and function in high levels of ROS and summarizes immunotherapy targeting ROS in MDSCs. The distinctive role of ROS in MDSCs will inspire us to widely apply the blocked oxidative stress strategy in targeting MDSC therapy to future clinical therapeutics.

Multilevel regulation of N6-methyladenosine RNA modifications: Implications in tumorigenesis and therapeutic opportunities.

N6-methyladenosine (m6A) RNA modification is widely perceived as the most abundant and common modification in transcripts. This modification is dynamically regulated by specific m6A "writers", "erasers" and "readers" and is reportedly involved in the occurrence and development of many diseases. Since m6A RNA modification was discovered in the 1970s, with the progress of relevant research technologies, an increasing number of functions of m6A have been reported, and a preliminary understanding of m6A has been obtained. In this review, we summarize the mechanisms through which m6A RNA modification is regulated from the perspectives of expression, posttranslational modification and protein interaction. In addition, we also summarize how external and internal environmental factors affect m6A RNA modification and its functions in tumors. The mechanisms through which m6A methylases, m6A demethylases and m6A-binding proteins are regulated are complicated and have not been fully elucidated. Therefore, we hope to promote further research in this field by summarizing these mechanisms and look forward to the future application of m6A in tumors.

Extracellular vesicle-encapsulated miR-10a-5p derived from MDSCs restrains germinal center B cells in experimental Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a progressive systemic autoimmune disease characterized by chronic inflammation of the exocrine glands, resulting in damage to the salivary and lacrimal glands. Our group and other researchers have reported that myeloid-derived suppressor cell-derived extracellular vesicles (MDSC-EVs) could attenuate the progression of autoimmune disease by impairing T-cell function. However, the effect of MDSC-EVs on B-cell function and the underlying mechanism remains largely unknown. In this study, we found that MDSC-EVs significantly attenuated the progression of experimental Sjögren's syndrome (ESS). Moreover, treatment with MDSC-EVs via intravenous injection markedly reduced the percentage of germinal center (GC) B cells in ESS mice. In vitro, MDSC-EVs could directly suppress the generation of GC B cells and the expression of B cell lymphoma 6 (Bcl-6) in B cells under GC B-cell-polarizing conditions. Mechanistically, miR-10a-5p carried by MDSC-EVs regulated the differentiation of GC B cells by targeting Bcl-6, and inhibition of miR-10a-5p in MDSC-EVs significantly reversed the effect of MDSC-EVs involved in alleviating the development of ESS. Taken together, our findings demonstrated that miR-10a-5p carried by MDSC-EVs inhibited the generation of B cells by targeting Bcl-6 and eventually alleviated the progression of ESS, which may provide novel therapeutic targets for the treatment of pSS.

Elevated cerebrospinal fluid YKL-40 levels in patients with anti-gamma-aminobutyric- acid-B receptor encephalitis.

OBJECTIVE: Anti-gamma-aminobutyric-acid-B receptor (GABAbR) encephalitis is a rare form of autoimmune encephalitis. Until now, there are few biomarkers that can indicate the severity and prognosis of patients with anti-GABAbR encephalitis. The objective of this study was to exam the changes of chitinase-3-like protein 1 (YKL-40) in patients with anti-GABAbR encephalitis. In addition, whether YKL-40 could indicate the disease severity was also evaluated. METHODS: The clinical features of 14 patients with anti-GABAbR encephalitis and 21 patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis were retrospectively studied. YKL-40 levels in serum and cerebral fluid (CSF) of patients were detected by enzyme-linked immunosorbent assay. The correlation of modified Rankin Scale (mRS) score of encephalitis patients and YKL40 levels were analyzed. RESULTS: YKL-40 levels in CSF were significantly higher in patients with anti-GABAbR encephalitis or anti-NMDAR encephalitis than those in controls. YKL-40 levels between these two encephalitis groups were not different. Moreover, YKL-40 levels in CSF from patients with anti-GABAbR encephalitis were positively correlated with the mRS score at admission and at 6-month follow-up. CONCLUSION: YKL-40 level is elevated in CSF from patients with anti-GABAbR encephalitis at early disease stage. YKL-40 may be a potential biomarker indicating the prognosis of patients with anti-GABAbR encephalitis.