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The treatment of depressive symptoms of bipolar disorder (BD) has received increasing attention. Recently, some studies have shown that bright light therapy (BLT) seems to be useful for BD depression. This meta-analysis is intended to further elucidate the role of BLT in depressive symptoms in patients with BD. Register of Systematic Reviews PROSPERO: CRD 420191 33642.Randomized controlled trials and cohort studies were retrieved in PubMed, Cochrane Library, EMbase, Web of Science, CINHAL, CBM, CNKI, VIP, and Wanfang from their foundation to March 2020, and other sources as supplement was also retrieved. Data were extracted after strict evaluation of literature quality by two researchers, and Meta-analysis was conducted on literatures that met the inclusion criteria. Meta-analysis was performed using Revman 5.3 software. In total, 12 studies including 847 patients with BD depression were included in our meta-analysis. A meta-analysis found significant differences between BLT and placebo for the following outcomes: (1) depression severity before and after BLT [SMD = -0.43, 95% CI (-0.73,-0.13), P<0.05] in RCT and [SMD = -2.12, 95% CI (-2.3,-1.94), P<0.05] in cohort studies.; (2) the efficacy of duration/timing of light therapy for depressive symptoms in BD [I2 = 85%, SMD = -1.88, 95% CI (-2.04, -1.71),P<0.05] and [I2 = 71%, SMD = -2.1,95% CI(-2.24, -1.96), P<0.05]; (3) the efficacy of different color/color temperatures for depressive symptoms in BD [I2 = 0%, SMD = -0.56, 95% CI (-0.92, -0.19), P<0.05] and [I2 = 97%, SMD = -1.74, 95% CI (-1.99, -1.49), P<0.05].We performed a subgroup meta-analysis of studies that used different light intensities. The results showed that light intensity≥5000 lux significantly reduced the severity of depression. And patients without psychotropic drugs revealed significantly decreased disease severity [I2 = 0%, SMD = -0.6, 95% CI (-1.06,-0.13), P<0.05]. Limitations of the study include studies only assessed short-term effects, and insufficient duration may underestimate adverse reactions and efficacy. Our results highlight the significant efficiency of BLT in the treatment of bipolar depression. Prospective studies with more rigorous design and consistent follow-up. [ABSTRACT FROM AUTHOR]

Background: Therapeutic glycoproteins have occupied an extremely important position in the market of biopharmaceuticals. N-Glycosylation of protein drugs facilitates them to maintain optimal conformations and affect their structural stabilities, serum half-lives and biological efficiencies. Thus homogeneous N-glycoproteins with defined N-glycans are essential in their application in clinic therapeutics. However, there still remain several obstacles to acquire homogeneous N-glycans, such as the high production costs induced by the universal utilization of mammalian cell expression systems, the non-humanized N-glycan structures and the N-glycosylation microheterogeneities between batches. Results: In this study, we constructed a Pichia pastoris (Komagataella phaffii) expression system producing truncated N-GlcNAc-modified recombinant proteins through introducing an ENGase isoform (Endo-T) which possesses powerful hydrolytic activities towards high-mannose type N-glycans. The results showed that the location of Endo-T in different subcellular fractions, such as Endoplasmic reticulum (ER), Golgi or cell membrane, affected their hydrolytic efficiencies. When the Endo-T was expressed in Golgi, the secreted IgG1-Fc region was efficiently produced with almost completely truncated N-glycans and the N-GlcNAc modification on the glycosite Asn297 was confirmed via Mass Spectrometry. Conclusion: This strategy develops a simple glycoengineered yeast expression system to produce N-GlcNAc modified proteins, which could be further extended to different N-glycan structures. This system would provide a prospective platform for mass production of increasing novel glycoprotein drugs. [ABSTRACT FROM AUTHOR]

The Ala-Pro-rich Antigen (Apa) from Mycobacterium tuberculosis is a mannosylated protein with immunogenic and antigenic properties. The O -mannosylation is essential for its biological function in the process of colonization and invasion of host cells by M. tuberculosis . In this work, the gene encoding Apa was cloned from M. tuberculosis and expressed in Pichia pastoris GS115. In shake-flasks, the recombinant Apa was secreted into the culture media and purified with a yield of 0.6 g/L. Both N - and O -glycans were found in recombinant Apa. In P. pastoris the known M. tuberculosis -derived O -glycosites of Apa were modified with short chains of mannose units, and a few additional glycosylation sites were also observed. Therefore, the recombinant Apa expressed in P. pastoris has similar but not identical O -mannose patterns to the native protein from M. tuberculosis . P. pastoris and mycobacteria share similarities in the protein O -glycosylation pathway. Thus P. pastoris could be a potential powerful expression system to produce mycobacteria-derived glycoproteins. [ABSTRACT FROM AUTHOR]

The primate connectome, possessing a characteristic global topology and specific regional connectivity profiles, is well organized to support both segregated and integrated brain function. However, the organization mechanisms shaping the characteristic connectivity and its relationship to functional requirements remain unclear. The primate brain connectome is shaped by metabolic economy as well as functional values. Here, we explored the influence of two competing factors and additional advanced functional requirements on the primate connectome employing an optimal trade-off model between neural wiring cost and the representative functional requirement of processing efficiency. Moreover, we compared this model with a generative model combining spatial distance and topological similarity, with the objective of statistically reproducing multiple topological features of the network. The primate connectome indeed displays a cost-efficiency trade-off and that up to 67% of the connections were recovered by optimal combination of the two basic factors of wiring economy and processing efficiency, clearly higher than the proportion of connections (56%) explained by the generative model. While not explicitly aimed for, the trade-off model captured several key topological features of the real connectome as the generative model, yet better explained the connectivity of most regions. The majority of the remaining 33% of connections unexplained by the best trade-off model were long-distance links, which are concentrated on few cortical areas, termed long-distance connectors (LDCs). The LDCs are mainly non-hubs, but form a densely connected group overlapping on spatially segregated functional modalities. LDCs are crucial for both functional segregation and integration across different scales. These organization features revealed by the optimization analysis provide evidence that the demands of advanced functional segregation and integration among spatially distributed regions may play a significant role in shaping the cortical connectome, in addition to the basic cost-efficiency trade-off. These findings also shed light on inherent vulnerabilities of brain networks in diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • A microfluidic analytical device based on plasmonic diatomite/Au micro-channel array. • Plasmonic stationary phase significantly improve the separation efficiency and visualization. • Ultra-high sensitivity for pyrene sensing down to 0.01 ppb by PTLC-DSERS. • Facile platform for point-of-care applications. Polycyclic aromatic hydrocarbons are a kind of persistent organic pollutants, which bring harmful effects to the ecological environment and human health. Therefore, it is critical to identify PAHs. In this study, we developed a highly efficient device for on-site identification of pyrene in edible oil using high performance plasmonic thin layer chromatography (PTLC) and dynamic surface-enhanced Raman spectroscopy (DSERS). PAHs in the mixture sample were efficiently separated on the PTLC plate and visualized under UV light, in which the plasmonic feature of the stationary phase could enhance the fluorescence of PAH. Then DSERS measurement was developed on a portable Raman spectrometer. The smaller size of Au NPs in the stationary phase could provide a lower theoretical plate height and provide higher separation efficiency. The sensitivity of the PTLC-DSERS method is down to 0.1 ppb, that nearly 4 orders of magnitude higher than current TLC-SERS method. The results indicate that this PTLC-DSERS method has the potential for on-site and sensitive identification of pyrene in the mixture. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cu was loaded on the S-doped TiO 2 by electroless plating method. The prepared Cu/S–TiO 2 exhibited high photocatalytic activity for hydrogen generation, and the yield is up to 7.5 mmol h − 1 g − 1 cat in methanol solution. Their physical structure and chemical properties were characterized by UV–Vis, XRD, XPS and EXAFS. The copper species were CuO and Cu 2 O, and the sample showed excellent visible light absorption ability. Comparing with the sample prepared by chemical reducing method, the electroless plated copper on S–TiO 2 was highly dispersed, which could facilitate photo-generated charges capture, transfer and separation. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress is a mechanism of cell death induced by seizures. Antioxidant compounds have neuroprotective effects due to their ability to inhibit free radical production. Autophagy is a process in which cytoplasmic components such as organelles and proteins are delivered to the lysosomal compartment for degradation, and plays an essential role in the maintenance of cellular homeostasis. The activity of autophagy is enhanced during oxidative stress. The objectives of this work were first to study the inhibitory action of antioxidant ascorbic acid on behavioral changes and brain damage induced by high doses of pilocarpine, then to study the effect of ascorbic acid on oxidative stress (MDA and SOD were used to estimate oxidative stress) and activated autophagy (beclin 1 was used to estimate autophagy) induced by seizures, aiming to further clarify the mechanism of action of this antioxidant compound. In order to determinate neuroprotective effects, we studied the effects of ascorbic acid (500mg/kg, i.p.) on the behavior and brain lesions observed after seizures induced by pilocarpine (340mg/kg, i.p., P340 model) in rats. Ascorbic acid injections prior to pilocarpine suppressed behavioral seizure episodes by increasing the latency to the first myoclonic, clonic and tonic seizure and decreasing the percentage of incidence of clonic and tonic seizures as well as the mortality rate. These findings suggested that oxidative stress can be produced and autophagy is increased during brain damage induced by seizures. In the P340 model, ascorbic acid significantly decreased cerebral damage, reduced oxidative stress and inhibited autophagy by reducing de novo synthesis of beclin 1. Antioxidant compound can exert neuroprotective effects associated with inhibition of free radical production and autophagy. These results highlighted the promising therapeutic potential of ascorbic acid in treatment for seizures. [Copyright &y& Elsevier]

Abstract: Intense poly(ADP-ribose) polymerase-1 (PARP-1) activation was implicated as a major cause of caspase-independent cell death in the hippocampal neuronal culture (HNC) model of acute acquired epilepsy (AE). The molecular mechanisms are quite complicated. The linkage among neuronal death, cellular nicotinamide adenine dinucleotide (NAD) levels, apoptosis-inducing factor (AIF) translocation, SIRT1 expression and activity were investigated here. The results showed that PARP-1 over-activation caused by Mg2+-free stimuli led to cellular NAD depletion which could block AIF translocation from mitochondria to nucleus and attenuate neuronal death. Also, SIRT1 deacetylase activity was reduced by Mg2+-free treatment, accompanied by elevated ratio of neuronal death, which could be rescued by NAD repletion. These data demonstrated that cellular NAD depletion and decline of SIRT1 activity play critical roles in PARP-1-mediated epileptic neuronal death in the HNC model of acute AE. [Copyright &y& Elsevier]

Abstract: In many cases, it is desirable to maintain the native status of the target glycoproteins when they are deglycosylated. However, most conventional deglycosylation process often causes the irreversible denaturation of the target glycoproteins. In the present study, we developed a deglycosylation method that could obtain the native deglycosylated proteins employing Png1p-ΔH1, which was confirmed to tolerate high concentration of dithiothreitol (DTT). To prove this process, ribonuclease B (RNase B) and Yeast carboxypeptidase (CPY) were employed as the targeting glycoproteins. Our results confirmed that both of them could be completely deglycosylated in the presence of high concentration DTT and could be refolded when DTT was removed. The circular dichroism spectroscopy (CD) measurement of refolded CPY and RNase B indicated that the structure of deglycosylated proteins had recovered their native status. This method offers the possibility of efficiently releasing N-linked glycans from glycoproteins and obtaining the native target proteins. [Copyright &y& Elsevier]

Abstract: Glucocorticoid-induced tumor necrosis factor receptor and its ligand (GITRL) are critically involved in the regulation of immune response. In this study, we aimed to generate bone marrow-derived dendritic cells (BMDCs) transfected with recombinant adenovirus expressing GITRL (pAd-GITRL-BMDCs) and explore their therapeutic efficacy in murine Lewis lung carcinoma. In vitro, pAd-GITRL-BMDCs greatly enhanced effector T cells proliferation but markedly abrogate the suppression of Treg cells. Moreover, vaccination with pAd-GITRL-BMDCs significantly retarded tumor growth, which was accompanied with increased IFN-γ-producing CD8+ T cells and markedly decreased Treg cells in vivo. These findings suggest GITRL could enhance the immune stimulation of DC and might facilitate the potential development of DCs-based anti-tumor therapies. [ABSTRACT FROM AUTHOR]

The effect of adding fluorinated Vulcan XC-72R into the microporous layer (MPL) of the cathode in a passive micro direct methanol fuel cell (μDMFC) has been investigated. Upon fluorination with fluoro-alkyl silane (FAS), the surface of XC-72R becomes more hydrophobic, as indicated by contact angle measurements. The performance of the membrane electrode assembly (MEA) is improved significantly when fluorinated Vulcan XC-72R is used in MPL of the cathode. The maximum power density of a passive μDMFC reached ca. 36.2 mW cm at room temperature, and the constant-current discharging test exhibits enhanced stability. Also observed is a decreased water transport coefficient (α), calculated from discharging test, attributable to the greater hydrophobicity resulting in higher liquid pressure on the cathode, which forces more water to flow back to the anode. Additionally, A.C. impedance analysis indicates that the improvement in performance results from the decrease of charge transfer resistance of the cathodic reaction. [ABSTRACT FROM AUTHOR]

Abstract: Status epilepticus (SE) is a severe clinical manifestation of epilepsy which causes brain damage. The pathological process and underlying mechanisms involved in the programmed cell death (PCD) are still not fully clear. In the current study, rats were induced SE by lithium–pilocarpine administration. Our data showed hippocampal neurons death appeared at 6h after SE and sustained for 7 days. By blotting the activation of μ-calpain and its specific cleavage of nonerythroid α-spectrin (αSpII) (145kDa) was evident at 1 and 3 days after SE, which coincided with Bid activation, apoptosis inducing factor (AIF) translocation and cytochrome c release from mitochondria, whereas, activated caspase-3 and caspase-3-specific fragments of αSpII (120kDa) predominantly appeared at 5 and 7 days after SE. Moreover, MDL-28170, a calpain inhibitor, partially rescued the neuron death and attenuated the expression of activated μ-calpain, cleavage of Bid (15kDa), AIF translocation and cytochrome c release. Taken together, our study indicated that μ-calpain mediated hippocampal neuron PCD is prior to caspase-3 activation. It functioned via translocation of Bid, AIF and cytochrome c release. [Copyright &y& Elsevier]

Abstract: Peptide:N-glycanase (PNGase) is an enzyme responsible for deglycosylation of misfolded glycoproteins in so-called endoplasmic reticulum-associated degradation (ERAD) system. In this study, we reported the molecular identification and characterization of SpPNGase (Schizosaccharomyces pombe PNGase). Enzymatic analysis revealed that SpPNGase deglycosylated the misfolded glycoproteins and distinguished native and denatured high-mannose glycoproteins in vitro. The deglycosylation activity was lost with the addition of chelating agent EDTA and was not restored by re-addition of metal ions. By construction of deletion mutant, we confirmed that N-terminal α-helix of SpPNGase was responsible for the protein–protein interaction. Combining the results from ternary structure prediction and dendrogram analysis, we suggested that the N-terminal α-helices of PNGase are derived from evolutionary motif/peptide fusion. [Copyright &y& Elsevier]

T-bet, a Th1-specific transcription factor, can promote the production of IFN-γ. IFN-γ is the principal Th1 effector cytokine and it has a crucial role in Th1 differentiation, which can drive the differentiation of naïve CD4+T cells into T-helper 1 (Th1) cells. In our study, a human T-bet gene was fused with a gene fragment encoding HIV-1 protein transduction domain in a bacterial expression vector to produce a Tat/T-bet fusion protein. The expressed and purified Tat/T-bet proteins were transduced efficiently into THP-1 cells in a time- and dose-dependent manner; when Tat/T-bet pretreated THP-1 cells were co-cultured with CD4+T cells, the IFN-γ level increased higher to about 7 pg/ml, 10-folds as compared with the normal level when tested at 48 hours. The results demonstrated that the Tat/T-bet fusion protein can be efficiently transduced into antigen-presenting cells (APCs) like THP-1 cells and then regulated Th1/Th2 balance, which may act as a potential tool for gene therapy. [ABSTRACT FROM AUTHOR]

Several recent epidemiological investigations raise serious questions about the health effects of high-dose supplements of Vitamin E (VE) in cigarette smokers. To examine these findings, a total of 96 C57BL/6 mice were randomly assigned to eight groups in a 2×4 factorial design (smoke vs. sham smoke and normal diet vs. 3 VE supplements). The mice were exposed to sidestream cigarette smoke (SSCS), at 0.4 mg total particulate matter/m3 air, from standard research cigarettes (1R4)/day or filtered room air at 30 min/day, 5 days/week, for 9 weeks through a nose-only exposure chamber. The American Institute of Nutrition 93G purified rodent diet was modulated with 75 (regular diet, 1-fold), 1050 (15-fold), 5550 (75-fold), and 11 175 (150-fold) IU dl-α-tocopherol acetate (α-TA)/kg as VE supplementation and provided ad libitum at an average intake rate of 4.11 g diet/mouse/day. This result demonstrated that SSCS exposure results in lung dysfunction, as indicated by a decrease of pulmonary dynamic compliance (Cdyn) and increase of lung resistance (RL), and body weight loss in mice fed with regular diet. These changes accompanied with increases of bronchoalveolar lavage (BAL) concentrations of cytokines interleukin (IL)-1β, IL-4 and IFN-γ, as well as hepatic lipid peroxidation. However, supplemental α-TA at the doses of &ges;1050 IU/kg diet prevented the SSCS-induced body weight loss and lung dysfunction. α-TA at &ges;5550 IU/kg significantly increased BAL levels of IL-2 and IL-4 in both the sham SSCS and the SSCS groups. Given at 5550 IU α-TA/kg, but not higher, mice elevated BAL IL-1β level if they were exposed to SSCS. Hepatic lipid peroxidation was decreased in a dose-dependent fashion with different α-TA supplements in both the sham SSCS and SSCS groups. Neither SSCS nor α-TA had an effect on lung permeability, BAL IL-6, splenic T and B lymphocyte proliferation and their T helper (Th)1 and Th2 cytokines measured among all groups. Data suggest that supplemental α-TA may be needed to counteract SSCS-induced oxidative stress, but that potential side effects introduced by high dosage of this synthetic compound should be considered. [Copyright &y& Elsevier]

Alveolar type II epithelial cells (AIIE) and pulmonary alveolar macrophages (PAM) are involved in pulmonary toxicity of JP-8 jet fuel exposure. To further elucidate their inflammatory mechanisms, the effect(s) of JP-8 jet fuel on cytokine secretion were examined in a transformed rat AIIE cell line (RLE-6TN) culture alone, primary PAM (from Fischer 344 rats) culture alone, and the co-culture of AIIE and primary PAM. A series of JP-8 jet fuel concentrations (0–0.8 μg/ml), which may actually be encountered in alveolar space of lungs exposed in vivo, were placed in cell culture for 24 h. Cultured AIIE alone secreted spontaneously interleukin (IL)-1β and -6 [below detectable limits for IL-10 and tumor necrosis factor-α (TNF-α)], whereas cultured PAM alone secreted IL-1β, -10, and TNF-α, in a concentration-dependent manner. These data suggest that the release of cytokines, not only from PAM but also from AIIE cells, may contribute to JP-8 jet fuel-induced inflammatory response in the alveolar space. However, the co-cultures of AIIE and PAM showed no significant changes in IL-1β, -6, and TNF-α at any JP-8 jet fuel concentration compared to control values. These cytokine levels in co-cultures of AIIE and PAM were inversely related to these of cultured AIIE or PAM alone. Interestingly, IL-10 levels in the co-culture system were concentration-dependently increased up to 1058% at JP-8 concentrations of 0.8 μg/ml, although under detectable limits in cultured AIIE alone and no significant concentration change in cultured PAM alone. It appears that PAM may possibly act via paracrine and/or autocrine pathways to signal AIIE cells to regulate cytokine release. [Copyright &y& Elsevier]

Our previous studies have demonstrated that JP-8 jet fuel aerosol inhalation induced lung injury and dysfunction. To further examine JP-8 jet fuelinduced inflammatory mechanisms, a total of 40 male C57BL/6 mice (young, 3.5 months; adult, 12 months; half in each age group) were randomly assigned to the exposure or control groups. Mice were nose-only exposed to room air or atmospheres of 1000 mg/m[sup 3] JP-8 jet fuel for 1 h/day for 7 days. Lung injury was assessed by pulmonary mechanics, respiratory permeability, lavaged cell profile, and chemical mediators in bronchoalveolar lavage fluid (BALF). The young and adult mice exposed to JP-8 jet fuel had similar values with regards to increased lung dynamic compliance, lung permeability, BALF cell count, and decreased PGE[sub 2]. However, there were several different responses between the young-versus-adult mice with respect to BALF cell differential, TNF-[sub α], and 8-iso-PGF[sub 2α] levels after exposure to JP-8 jet fuel. These data suggest that JP-8 jet fuel may have different inflammatory mechanisms leading to lung injury and dysfunction in the younger-versus-adult mice. 2. [ABSTRACT FROM AUTHOR]

Production of glycoprotein therapeutics in Chinese hamster ovary (CHO) cells is limited by the cells' generic capacity for N-glycosylation, and production of glycoproteins with desirable homogeneous glycoforms remains a challenge. We conducted a comprehensive knockout screen of glycosyltransferase genes controlling N-glycosylation in CHO cells and constructed a design matrix that facilitates the generation of desired glycosylation, such as human-like α2,6-linked sialic acid capping. This engineering approach will aid the production of glycoproteins with improved properties and therapeutic potential. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is dynamically regulated by methyltransferases (termed "writers") and demethylases (referred to as "erasers"), facilitating a reversible modulation. Changes in m6A levels significantly influence cellular functions, such as RNA export from the nucleus, mRNA metabolism, protein synthesis, and RNA splicing. They are intricately associated with a spectrum of pathologies. Moreover, dysregulation of m6A modulation has emerged as a promising therapeutic target across many diseases. m6A plays a pivotal role in controlling vital downstream molecules and critical biological pathways, contributing to the pathogenesis and evolution of numerous conditions. This review provides an overview of m6A demethylases, explicitly detailing the structural and functional characteristics of FTO and ALKBH5. Additionally, we explore their distinct involvement in various diseases, examine factors regulating their expression, and discuss the progress in inhibitor development. [ABSTRACT FROM AUTHOR]

The flexible SERS substrate were prepared base on regenerated cellulose fibers, in which the Au nanoparticles were controllably assembled on fiber through electrostatic interaction. The cellulose fiber was regenerated from waste paper through the dry-jet wet spinning method, an eco-friendly and convenient approach by using ionic liquid. The Au NPs could be controllably distributed on the surface of fiber by adjusting the conditions during the process of assembling. Finite-difference time-domain theoretical simulations verified the intense local electromagnetic fields of plasmonic composites. The flexible SERS fibers show excellent SERS sensitivity and adsorption capability. A typical Raman probe molecule, 4-Mercaptobenzoicacid (4-MBA), was used to verify the SERS cellulose fibers, the sensitivity could achieve to 10−9 M. The flexible SERS fibers were successfully used for identifying dimetridazole (DMZ) from aqueous solution. Furthermore, the flexible SERS fibers were used for detecting DMZ from the surface of fish by simply swabbing process. It is clear that the fabricated plasmonic composite can be applied for the identifying toxins and chemicals. [ABSTRACT FROM AUTHOR]

The article describes a case of disseminated plasmacytomas in multiple myeloma in a 47-year-old man. The patient presented with a 25-day history of chest wall masses. Computed tomography angiography images revealed round or spindle masses around the sternum and in both pleural regions without obvious enhancement, while whole-body positron emission tomography/computed tomography (PET/CT) showed slight to mild uptake of fluorodeoxyglucose (FDG) with SUVmax of 1.5 to 3.2 for soft tissue lesions.

Netrin-1 is a member of the laminin-like protein family and was initially identified as a potent chemotactic molecule involved in axonal guidance and cell migration during embryonic development. Many studies have focused on the non-neural effects of netrin-1, and the results revealed that netrin-1 may be extensively involved in the regulation of angiogenesis, inflammation, tissue remodeling, and cancer. The pathogenic or protective effect of netrin-1 suggests that it may be a potential therapeutic target in multiple diseases. Netrin-1 plays different roles by interacting with its receptors, such as deleted in colorectal cancer (DCC)/neogenin and the uncoordinated-5 homolog family members (UNC5). Interestingly, contradictory actions in certain physiological pathways serve to highlight its manifold and often opposite effects on numerous physiological and pathophysiological processes. Netrin-1 regulates inflammation and leukocyte infiltration, suggesting roles for netrin-1 in the immune response. In this study, we review recent advances in the understanding of netrin-1 and its receptors in many inflammatory diseases and look forward to the bioavailability of netrin-1 for the future. [Display omitted] • Netrin-1 contains a highly conserved N-terminal LN domain, domain V and a small positively charged C-terminal domain. • The netrin-1-receptor axis is usually dynamically fine-tuned at specific locations and times. • Netrin-1 engages several different receptors to activate chemotropic responses and adhesive mechanisms in non-neural systems. • Netrin-1 involved in angiogenesis, leukocyte migration, and macrophage phenotype switching. [ABSTRACT FROM AUTHOR]

Aberrant accumulation of circulating follicular helper T cells (cTfh) has been found in the peripheral blood mononuclear cells (PBMCs) of Graves' disease (GD) patients. However, the underlying mechanism that contributes to the imbalance of cTfh cells remains unknown. Previously, studies described a GD‐related circular RNAs (circRNAs)‐circZNF644 that might be associated with cTfh cells. This study aimed to investigate the role of circZNF644 on cTfh cells in GD patients. Here, we found that circZNF644 was highly stable expression in the PBMCs of GD patients, which was positively correlated with the serum levels of TSH receptor autoantibodies (TRAb). Knockdown of circZNF644 caused a reduction of the proportion of cTfh cells in vitro. Mechanistically, circZNF644 served as a ceRNA for miR‐29a‐3p to promote ICOS expression, resulting in increased cTfh cells. In the PBMCs of GD patients, circZNF644 expression was positively correlated with ICOS expression and the percentage of cTfh cells, but negatively related to miR‐29a‐3p expression. Additionally, a strong relationship between circZNF644 and IL‐21 was revealed in GD patients, and silencing of circZNF644 inhibited IL‐21 expression. Our study elucidated that elevated expression of circZNF644 is a key feature in the development of GD and may contribute to the pathogenic role of cTfh cells in GD. [ABSTRACT FROM AUTHOR]

Follicular regulatory T (Tfr) cells are the regulatory T cell subset mainly localized in the germinal center (GC), acting as modulators of GC responses. They can disrupt Tfh cell- and B cell-linked recognition, induce Tfh apoptosis, and suppress B cell function. Evidences show that dysregulated Tfr cells are associated with the disease activity index and serum autoantibody levels, influencing the development of systemic lupus erythematosus (SLE). This review focuses on the interaction among Tfr, Tfh, and B cells, summarizes the characterization and function of Tfr cells, concludes the imbalance of CD4+T subsets in SLE, and presents potential therapies for SLE. In general, we discuss the roles of Tfr cells in the progress of SLE and provide potential treatments. [ABSTRACT FROM AUTHOR]

As the main protein components of chromatin, histones play central roles in gene regulation as spools of winding DNA. Histones are subject to various modifications, including phosphorylation, acetylation, glycosylation, methylation, ubiquitination and citrullination, which affect gene transcription. Histone citrullination, a posttranscriptional modification catalyzed by peptidyl arginine deiminase (PAD) enzymes, is involved in human carcinogenesis. In this study, we highlighted the functions of histone citrullination in physiological regulation and tumors. Additionally, because histone citrullination involves forming neutrophil extracellular traps (NETs), the relationship between NETs and tumors was illustrated. Finally, the clinical application of histone citrullination and PAD inhibitors was discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: This Phase I study evaluated the safety, tolerability, food effects, pharmacodynamics, and pharmacokinetics of donafenib in patients with advanced solid tumours.Methods: Eligible patients received a single dose of donafenib (50 mg, 100 mg, 200 mg, 300 mg, or 400 mg) and were then observed over a 7-day period; thereafter, each patient received the corresponding dose of donafenib twice daily for at least 4 weeks. Safety assessment and pharmacokinetic sampling were performed for all patients at the given time points; preliminary tumour response was also assessed.Results: Twenty-five patients were enrolled in this study. Gastrointestinal reactions were the most common treatment-related adverse event, followed by skin toxicity. The maximum tolerated dose (MTD) was 300 mg bid. The dose-limiting toxicities (DLTs) were grade 3 diarrhoea and fatigue at 300 mg bid and grade 3 skin toxicity at 400 mg bid. In the dose range of 100 ~ 400 mg, T1/2 and AUC0-t after multiple doses were 26.9 ~ 30.2 h and 189 ~ 356 h*μg/mL, respectively. Food did not have a significant effect on the pharmacokinetics of donafenib. Twenty-one patients were assessed for efficacy, and two patients achieved a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST), with a disease control rate of 57.1%.Conclusion: Oral donafenib was generally well tolerated and appeared to provide some clinical benefits; adverse events were manageable. Based on the results of this study, oral donafenib at 200 mg ~ 300 mg twice daily is recommended for further studies. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • MDSCs induce immunosuppression and drive tumor immune escape in the TME. • Signaling pathways in the TME impact histone modifications that regulate MDSC differentiation and function. • Epigenetic interventions targeting histone modifications hold potential for reversing MDSC-induced immunosuppression. [ABSTRACT FROM AUTHOR]

Complex carbohydrates serve a wide range of biological functions in cells and tissues, and their biosynthesis involves more than 200 distinct glycosyltransferases (GTfs) in human cells. The kinetic properties, cellular expression patterns and subcellular topology of the GTfs direct the glycosylation capacity of a cell. Most GTfs are ER or Golgi resident enzymes, and their specific subcellular localization is believed to be distributed in the secretory pathway according to their sequential role in the glycosylation process, although detailed knowledge for individual enzymes is still highly fragmented. Progress in quantitative transcriptome and proteome analyses has greatly advanced our understanding of the cellular expression of this class of enzymes, but availability of appropriate antibodies for in situ monitoring of expression and subcellular topology have generally been limited. We have previously used catalytically active GTfs produced as recombinant truncated secreted proteins in insect cells for generation of mouse monoclonal antibodies (mAbs) to human enzymes primarily involved in mucin-type O-glycosylation. These mAbs can be used to probe subcellular topology of active GTfs in cells and tissues as well as their presence in body fluids. Here, we present several new mAbs to human GTfs and provide a summary of our entire collection of mAbs, available to the community. Moreover, we present validation of specificity for many of our mAbs using human cell lines with CRISPR/Cas9 or zinc finger nuclease (ZFN) knockout and knockin of relevant GTfs. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death worldwide due to its late diagnosis and poor outcome. Immunotherapy is becoming more and more encouraging and promising in lung cancer therapy. Myeloid-derived suppressor cells (MDSCs) are the main tumor suppressor factors, and the treatment strategy of targeting MDSCs is gradually emerging. In this review, we summarize what is currently known about the role of MDSCs in lung cancer. In view of the emerging importance of MDSCs in lung cancer, the treatment of targeting MDSCs will be useful to the control of the development and progression of lung cancer. However, the occurrence, metastasis, and survival of cancer is the result of multiple factors and multiple mechanisms, so combined treatments using different strategies will become the major therapy method for lung cancer in the future. [ABSTRACT FROM AUTHOR]

• A novel coaxial parallel five-link mechanism classification method is proposed. • The leg linkage design problem is combined with motion planning of robot's body. • An alternating optimization approach for jumping robot leg design is proposed. • The experiments on biped robot show a jumping performance comparable to human. Jumping, as widely observed amongst agile terrestrial creatures, is regarded as an indispensable ability for legged robots with high-performance in dealing with complex environments. This study presents a novel leg design methodology for jumping robot using the alternating iteration approach that optimizes the leg linkage and the specified jumping motion to completely leverage the capability of the actuator. First, a coaxial parallel five-link mechanism (CPFM) classification method was proposed to extract feasible candidates of leg configuration to alleviate the intensely searching complexity due to multi-link singularity. An alternating optimization paradigm was developed by elaborately combining the motion planning (MP) and the linkage design (LD) to generate a favorable leg with a CPFM morphology. The MP task was constructed to maximize the jumping distance of the robot while the LD task was proposed to minimize the peak demand of the actuators. Finally, a sagittal jumping robot prototype was developed based on the optimal results from the proposed paradigm. We obtained a horizontal jumping performance of 1.8 times the maximum leg length, which is comparable to the natural performance of a human. [ABSTRACT FROM AUTHOR]

Background Benign rolandic epilepsy ( BRE) is one of the most common focal epilepsies in childhood, but less typical clinical presentations may lead to misdiagnosis and incorrect treatment. The focus of this study was therefore to retrospectively investigate the less typical features of BRE in Chinese children. Methods Data on 316 Chinese children with BRE were collected and analyzed. Results A total of 7.3% of children complained of tension, fear and terror at the onset of a seizure, and 5.4% had been misdiagnosed with mesial temporal lobe epilepsy. Approximately 12.3% had post-ictal Todd's paresis, with 6.6% having been misdiagnosed and given incorrect treatment. Nineteen children (6%) had neuroradiologic abnormalities, which could lead to a diagnosis of symptomatic epilepsy. Twenty-five patients (8.0%) had cognitive deficits. Conclusions Greater recognition of, and further investigation into, the spectrum of BRE are needed. [ABSTRACT FROM AUTHOR]

The spike protein of SARS-CoV-2 has been widely used as an effective vaccine immunogen, although some limitations still remain. Herein, O-GalNAc glycosylated RBD (Tn-RBD) was synthesized as an antigen via in vitro glycosylation reactions. The inhibition ability against hACE2 binding of antibodies induced with Tn-RBD was 30–40% increased compared to that induced with RBD. This result implies that Tn-glycosylation might play important roles in the immunogenicity of the RBD protein, which should be considered in the design of novel vaccines to fight against COVID-19. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by multiorgan involvement and marked variability in clinical presentation. SLE pathogenesis includes regulatory T cell dysfunction and antinuclear antibody production. Mammalian target of rapamycin (mTOR), a serine/threonine kinase in the phosphoinositide 3-kinase (PI3K)-related kinase family, is a therapeutic target for autoimmune diseases such as SLE. Rapamycin, an inhibitor of the mTOR signaling pathway, is a macrolide antibiotic with potent immunosuppressive, antiproliferative and antifibrotic effects. Recently, an increasing number of studies have investigated the role of mTOR in regulatory T (Treg) cells and its impact on SLE pathogenesis. This review aims to systematically summarize the role of the mTOR signaling pathway in SLE pathogenesis, Treg cell dysfunction and SLE treatment. • mTOR signaling is essential for Treg cell differentiation. • Treg cell dysfunction is important in the pathogenesis of SLE. • The inhibition of mTOR signaling is critical for the treatment of SLE by regulating Treg cell function. [ABSTRACT FROM AUTHOR]

Background: Recent studies have revealed a role of the ligand for glucocorticoid-induced TNFR family-related protein (GITRL) in mediating functional dysregulations of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of primary Sjögren syndrome (pSS), but the underlying molecular mechanism is largely unclear. In this study, we aimed to elucidate GITRL-mediated signaling pathways in MDSCs during the development of experimental SS (ESS). Methods: MDSCs were stimulated with recombinant GITRL, the activation of PTEN, AKT and STAT3 in MDSCs was analyzed by Western blot. MDSCs with different treatment were adoptively transferred to ESS mice. ELISA was used to detect the level of autoantibodies. Proportions of Th1 and Th17 cells were examined by flow cytometry. Histological evaluation of glandular destruction was analyzed by hematoxylin and eosin (HE) staining. The interaction of GITR, TRAF3 and PP2A was detected by CoIP. Results: Upon the engagement of GITR on MDSCs, PTEN was activated and led to the inhibition of downstream AKT/STAT3 signaling pathway, therefore, resulting in the impaired immunosuppressive function of MDSCs. In ESS mice, blocking the activity of PTEN could efficiently restore the immunomodulatory effect of MDSCs and alleviate the progression of ESS. Furthermore, TRAF3 was found to bind to GITR, and then recruited PP2A to dephosphorylate PTEN, thus enhancing the activity of PTEN. Conclusion: This study elucidated the molecular mechanism underlying the effect of GITRL in regulating the function of MDSCs, which may provide a new therapeutic target for the treatment of pSS. [ABSTRACT FROM AUTHOR]

Objective: Myeloid-derived suppressor cells (MDSCs) are a major immunosuppressive population in the tumor microenvironment,inhibiting anti-tumor immune response and exerting pro-tumorigenic effect. CCAAT/enhancer-binding protein beta (C/EBPβ), a key transcription factor indispensable for myelopoiesis, plays a fundamental role in regulating expansion and activation of MDSCs. Lysine acetylation can regulate functions of transcription factors. However, the role of C/EBPβ acetylation modification in MDSCs has not been reported. Materials and methods: MDSCs derived from the spleens of tumor-bearing mice (TB-SP-MDSCs) were isolated by immunomagnetic beads. Bone marrow derived MDSCs were induced by IL-6 and GM-CSF. Western-blot was used to detect the expression of P300 and co-immunoprecipitation (CO-IP) was used to detect the C/EBPβ acetylation in MDSCs. Inhibitor C646 was used to specificly inhibit P300 activity. Results: In this study, we found that C/EBPβ was acetylated by acetyltransferase P300 in MDSCs. A P300-mediated C/EBPβ acetylation enhanced C/EBPβ transactivation activity on arginase 1 (Arg-1) gene promoter. Inhibition of P300 activity downregulated the inhibitory effects of MDSCs in vitro and attenuated pro-tumorigenic effects of MDSCs in vivo. Additionally, IL-6 from tumor microenvironment could upregulate the expression of P300 and enhance C/EBPβ acetylation in MDSCs. Conclusion: In general, a P300-mediated C/EBPβ acetylation enhanced C/EBPβ transactivation activity on Arg-1 promoter, thus promoting immunosuppressive function of MDSCs. In view of the critical role of P300 in regulating MDSCs, P300 might be a potential target of anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A), the most abundant modification in mRNAs, affects the fate of the modified RNAs at the post-transcriptional level and participants in various biological and pathological processes. Increasing evidence shows that m6A modification plays a role in the progression of many malignancies, including colorectal cancer (CRC). As the only catalytic subunit in methyltransferase complex, methyltransferase-like 3 (METTL3) is essential to the performance of m6A modification. It has been found that METTL3 is associated with the prognosis of CRC and significantly influences various aspects of CRC, such as cell proliferation, invasion, migration, metastasis, metabolism, tumor microcirculation, tumor microenvironment, and drug resistance. The relationship between METTL3 and gut-microbiota is also involved into the progression of CRC. Furthermore, METTL3 might be a viable target for CRC treatment to prolong survival. In this review, we comprehensively summarize the function of METTL3 in CRC and the underlying molecular mechanisms. We aim to deepen understanding and offer new ideas for diagnostic biomarkers and therapeutic targets for colorectal cancer. [ABSTRACT FROM AUTHOR]

Figure 6. Schematic illustration of the activated NLRP3 inflammasome and the therapeutic effects of MCC950 in anti-NMDAR encephalitis. Overactivated NLRP3 inflammasome and inflammatory response were detected in anti-NMDAR encephalitis mice model induced by active immunization, companied with the overactivation of microglia. MCC950 had the potential protective effect to inhibit NLRP3 associated inflammatory cascade and alleviate the cognitive deficits in anti-NMDAR encephalitis mice model. NLRP3, the nucleotide-binding oligomerization domain like receptor family pyrin domain-containing 3; ASC, Apoptosis-associated speck-like protein containing a CARD; NEA, anti-NMDAR encephalitis mice model induced by active immunization; IL1β, interleukin 1β; IL18, interleukin 18. [Display omitted] • Cognitive dysfunction was found in the anti-NMDAR encephalitis mice model induced by active immunization with peptide GluN1 356–385. • Overactivated NLRP3 inflammasome were firstly uncovered in the anti-NMDAR encephalitis mice model, leading to microglia overactivation and inflammatory cascade reaction. • MCC950, a specific inhibitor of the NLRP3 inflammasome, alleviated the inflammatory response and cognitive dysfunction in the anti-NMDAR encephalitis mice. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neurological disorder, characterized by cognitive deficits as one of its vital features. The nucleotide-binding oligomerization domain-like receptor (NLRP3) inflammasome is a key contributor to neuroinflammation and cognitive deficits in neurological diseases. However, the underlying mechanism of anti-NMDAR encephalitis remains unclear, and the biological function of the NLRP3 inflammasome in this condition has not been elucidated. In this study, a mouse model of anti-NMDAR encephalitis was induced by active immunization with the GluN1 356–385 peptide (NEA model). The NLRP3 inflammasome in the hippocampus and temporal cortex was investigated using real-time quantitative PCR (RT-qPCR), western blotting, and immunofluorescence staining. The impact of MCC950 on cognitive function and NLRP3 inflammation was assessed. Confocal immunofluorescence staining and Sholl analysis were employed to examine the function and morphology of microglia. In the current study, we discovered overactivation of the NLRP3 inflammasome and an enhanced inflammatory response in the NEA model, particularly in the hippocampus and temporal cortex. Furthermore, significant cognitive dysfunction was observed in the NEA model. While, MCC950, a selective inhibitor of the NLRP3 inflammasome, sharply attenuated the inflammatory response in mice, leading to mitigated cognitive deficits of mice and more regular arrangements of neurons and reduced number of hyperchromatic cells were also observed in the hippocampus area. In addition, we found that the excess elevation of NLRP3 inflammasome was mainly expressed in microglia accompanied with the overactivation of microglia, while MCC950 treatment significantly inhibited the increased number and activated morphological changes of microglia in the NEA model. Altogether, our study reveals the vital role of overactivated NLRP3 signaling pathway in aggravating the inflammatory response and cognitive deficits and the potential protective effect of MCC950 in anti-NMDAR encephalitis. Thus, MCC950 represents a promising strategy for anti-inflammation in anti-NMDAR encephalitis and our study lays a theoretical foundation for it to become a clinically targeted drug. [ABSTRACT FROM AUTHOR]

In recent years, there has been a significant increase in the incidence of metabolic-associated fatty liver disease (MAFLD), which has been attributed to the increasing prevalence of type 2 diabetes mellitus (T2DM) and obesity. MAFLD affects more than one-third of adults worldwide, making it the most prevalent liver disease globally. Moreover, MAFLD is considered a significant risk factor for hepatocellular carcinoma (HCC), with MAFLD-related HCC cases increasing. Approximately 1 in 6 HCC patients are believed to have MAFLD, and nearly 40 % of these HCC patients do not progress to cirrhosis, indicating direct transformation from MAFLD to HCC. N6-methyladenosine (m6A) is commonly distributed in eukaryotic mRNA and plays a crucial role in normal development and disease progression, particularly in tumors. Numerous studies have highlighted the close association between abnormal m6A modification and cellular metabolic alterations, underscoring its importance in the onset and progression of MAFLD. However, the specific impact of m6A modification on the progression of MAFLD to HCC remains unclear. Can targeting m6A effectively halt the progression of MAFLD-related HCC? In this review, we investigated the pivotal role of abnormal m6A modification in the transition from MAFLD to HCC, explored the potential of m6A modification as a therapeutic target for MAFLD-related HCC, and proposed possible directions for future investigations. [Display omitted] • It analyzes how aberrant m6A modifications contribute to the progression of MAFLD to HCC. • It explores the potential of m6A modification as a therapeutic target and biomarker for MAFLD-HCC. • It elucidates paradoxical m6A regulation and proposes a new model for future research. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy, such as PD-1/PD-L1 blockade, has shown promising clinical efficacy in patients with various types of tumors. However, the response to PD-1/PD-L1 blockade in a majority of malignancies is limited, indicating an urgent need for a deeper understanding of the mechanisms of PD-1/PD-L1 axis-mediated tumor tolerance. As the most abundant immune cells in the tumor stroma, macrophages display multiple phenotypes and functions in response to the stimuli of the tumor microenvironment. PD-1/PD-L1 has been demonstrated to be highly expressed in tumor-associated macrophages (TAMs), and TAM polarization has been shown to be important during tumor progression. In this review, we outline the relationship between TAM PD-1/PD-L1 expression and polarizations, summarize the involvement of M2 TAMs in PD-1/PD-L1-mediated T-cell exhaustion, and discuss improved approaches for overcoming PD-1/PD-L1 blockade resistance by inducing M2/M1 switching of TAMs. [Display omitted] • TAMs express both the receptor PD-1 and PD-L1 highly within tumor tissues. • PD-1/PD-L1 axis induces TAMs to polarize toward an M2 phenotype. • M2 TAMs contribute to PD-1/PD-L1 blockade resistance by inducing T-cell exclusion. • M2 TAMs contribute to PD-1/PD-L1 blockade resistance by inhibiting T-cell functions. • M2/M1 switching of TAMs is a promising strategy for improving tumor immunotherapy. [ABSTRACT FROM AUTHOR]

The regulation of T cell response depends on co-inhibitory pathways that serve to control immune-mediated tissue damage and resolve inflammation by modulating the magnitude and duration of immune response. In this process, the axis of T-cell-expressed programmed death-1 (PD-1) and its ligands (PD-L1 and PD-L2) play a key role. While the PD-1/PD-L pathway has received considerable attention for its role in the maintenance of T cell exhaustion in cancer and chronic infection, the PD-1/PD-L pathway also plays diverse roles in regulating host immunity beyond T cell exhaustion. In this review, we will discuss emerging concepts in co-stimulatory functions of PD-1/PD-L pathway on T cell- and B cell response and explore the potential underlying mechanisms. In addition, based on the elevated expression of PD-1 and its ligands in local inflamed tissues, we further discussed the role of PD-1/PD-L pathway in autoimmune diseases. [Display omitted] • The inhibitory or co-stimulatory function of PD-1/PD-L pathway is influenced by many factors. • PD-1/PD-L pathway also contributes to T cell and B cell development and activation. • The role of PD-1/PD-L pathway is involved in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects multiple systems. Its clinical manifestation varies across patients, from skin mucosa to multiorgan damage to severe central nervous system involvement. The exosome has been shown to play an important role in the pathogenesis of autoimmune diseases, including SLE. We review the recent knowledge of exosomes, including their biology, functions, mechanism, and standardized extraction and purification methods in SLE, to highlight potential therapeutic targets for SLE. [ABSTRACT FROM AUTHOR]

Abnormal expression of mucin-type O-glycosylation has been reported to be associated with a variety of human cancers including gliomas. However, little is known about its contribution to the malignancy of Glioblastoma Multiforme (GBM), the deadliest form of brain tumors. Here, we conducted a detailed analysis of the expression profiles of GALNT gene family, which encode polypeptide-N-acetyl-galactosaminyltransferases (GalNAc-Ts) and are responsible for initiating O-glycans, both in the Cancer Genome Atlas (TCGA) and in the Chinese Glioma Genome Atlas (CGGA) databases. We discovered that GALNT12 is the only member within the GALNT family, whose expression demonstrated significant correlation with a worse prognosis of GBM. Genetic knockdown (KD) and knockout (KO) of GALNT12 in U87 MG, a representative GBM cell line with high GALNT12 expression, confirmed that GALNT12 deficiency leads to decreased cell proliferation, migration and invasion. Mechanism study revealed that GALNT12 KD and KO decreased the level of epidermal growth factor (EGF) and consequently attenuated Akt signaling within the cell. In summary, our results indicated that GALNT12 facilitates the malignant characteristics of GBM by influencing the PI3K/Akt/mTOR axis and may serve as a novel prognosis biomarker and a potential therapeutic target of GBM. • GALNT12 expression significantly correlates with poor prognosis in GBM patients. • Downregulation of GALNT12 leads to decreased proliferation, migration and invasion of GBM cells. • EGF expression and PI3K/Akt signaling pathway are modulated by GALNT12 in GBM cell lines. [ABSTRACT FROM AUTHOR]

RNA N6-methyladenosine (m6A) modification is abundant in eukaryotes, bacteria and archaea. It is an RNA modification mainly existing in messenger RNA (mRNAs) and has a significant effect on the metabolism and function of mRNAs. m6A modification is controlled by three types of proteins, namely methyltransferase as the "writers", demethylase as the "erasers", and specific m6A recognized protein (YTHDF1–3) as the "readers". Recent studies have shown that m6A modification plays an important role in cancer, viral infection and autoimmune diseases. In this review, we will elaborate on the m6A modifications in the homeostasis and differentiation of T cells. Then we will further summarize the effects of m6A modification on the T cell responses and T cell-mediated autoimmune diseases. This will advance T cell epigenetics research and provide potential biomarkers and therapeutic targets for autoimmune diseases. [Display omitted] • RNA m6A modification is an important regulator of T cells homeostasis and differentiation. • Regulation of m6A modification in antigen presenting cells may control T cell differentiation and function. • m6A modification involved in T cell mediated autoimmune diseases. [ABSTRACT FROM AUTHOR]

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. Lu et al. show that, in addition to direct contact, Tfh cells can promote B cell differentiation and antibody production by releasing CD40L-containing sEVs, which may play a key role in the development of collagen-induced arthritis (CIA) in mice. [Display omitted] • Tfh cells promote B cell differentiation and antibody production by secreting sEVs • CD40L is involved in Tfh-sEVs-mediated B-cell response, which is regulated by SNX27 • Tfh-sEVs exacerbate the severity of CIA by enhancing B cell responses [ABSTRACT FROM AUTHOR]

[Display omitted] • Excessive mitochondrial fission was demonstrated in mice model of anti-NMDAR encephalitis, leading to mitochondrial dysfunction. • Blockade of the autophagic flux was found in mice model of anti-NMDAR encephalitis, resulting in accumulation of the fragmented mitochondria. • The overactivated mTOR signaling pathway exerts dual regulation over mitochondrial fission and autophagy. • Rapamycin, the specific inhibitor of mTOR signaling pathway, alleviates mitochondrial dysfunction and behavioral disorders 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. [ABSTRACT FROM AUTHOR]

B cells play a pivotal role in the pathogenesis of autoimmune disease (AD) by the production of autoantibodies, secretion of cytokines and presentation of autoantigens. As a pro-survival factor mainly produced by myeloid cells, B cell-activating factor (BAFF) maintains B cell maturation and homeostasis at various B cell differentiation stages. Under autoimmune conditions, BAFF acts on autoreactive B cells that have escaped checkpoint apoptosis from negative selection. Numerous studies have shown increased levels of BAFF in patients with ADs and in mouse models with ADs wherein the production of autoantibodies is a prominent feature of immunopathology. Compelling evidence has indicated a key function of BAFF in driving autoreactive B cell response during autoimmune progression. Recent clinical studies have demonstrated BAFF as a therapeutic target in various ADs. Here, we review recent findings on BAFF expression and its effector mechanisms in autoimmune pathogenesis as well as newly developed therapeutic targeting of BAFF in the treatment of ADs. [Display omitted] [ABSTRACT FROM AUTHOR]