Palmitoylation of NLRP3 Modulates Inflammasome Activation and Inflammatory Bowel Disease Development.

Aberrant activity of NLRP3 has been shown associations with severe diseases. Palmitoylation is a kind of protein post-translational modification, which has been shown to regulate cancer development and the innate immune system. Here, we showed that NLRP3 is palmitoylated at Cys419 and that palmitoyltransferase ZDHHC17 is the predominant enzyme that mediates NLRP3 palmitoylation and promotes NLRP3 activation by interacting with NLRP3 and facilitating NIMA-related kinase 7 (NEK7)-NLRP3 interactions. Blockade of NLRP3 palmitoylation by a palmitoylation inhibitor, 2-bromopalmitate, effectively inhibited NLRP3 activation in vitro. Also, in a dextran sulfate sodium-induced colitis model in mice, 2-bromopalmitate application could attenuate weight loss, improve the survival rate, and rescue pathological changes in the colon of mice. Overall, our study reveals that palmitoylation of NLPR3 modulates inflammasome activation and inflammatory bowel disease development. We propose that drugs targeting NLRP3 palmitoylation could be promising candidates in the treatment of NLRP3-mediated inflammatory diseases.

Tailam paramyxovirus C protein inhibits viral replication.

Jeilongviruses are emerging single-stranded negative-sense RNA viruses in the Paramyxoviridae family. Tailam paramyxovirus (TlmPV) is a Jeilongvirus that was identified in 2011. Very little is known about the mechanisms that regulate viral replication in these newly emerging viruses. Among the non-structural viral proteins of TlmPV, the C protein is predicted to be translated from an open reading frame within the phosphoprotein gene through alternative translation initiation. Though the regulatory roles of C proteins in virus replication of other paramyxoviruses have been reported before, the function of the TlmPV C protein and the relevant molecular mechanisms have not been reported. Here, we show that the C protein is expressed in TlmPV-infected cells and negatively modulates viral RNA replication. The TlmPV C protein interacts with the P protein, negatively impacting the interaction between N and P, resulting in inhibition of viral RNA replication. Deletion mutagenesis studies indicate that the 50 amino-terminal amino acid residues of the C protein are dispensable for its inhibition of virus RNA replication and interaction with the P protein.IMPORTANCETailam paramyxovirus (TlmPV) is a newly identified paramyxovirus belonging to the Jeilongvirus genus, of which little is known. In this work, we confirmed the expression of the C protein in TlmPV-infected cells, assessed its function, and defined a potential mechanism of action. This is the first time that the existence of a Jeilongvirus C protein has been confirmed and its role in viral replication has been reported.

An ascidian Polycarpa aurata-derived pan-inhibitor against coronaviruses targeting Mpro.

Coronaviruses (CoVs) are responsible for a wide range of illnesses in both animals and human. The main protease (Mpro) of CoVs is an attractive drug target, owing its critical and highly conserved role in viral replication. Here, we developed and refined an enzymatic technique to identify putative Mpro inhibitors from 189 marine chemicals and 46 terrestrial natural products. The IC50 values of Polycarpine (1a), a marine natural substance we studied and synthesized, are 30.0 ± 2.5 nM for SARS-CoV-2 Mpro and 0.12 ± 0.05 µM for PEDV Mpro. Our research further demonstrated that pretreatment with Polycarpine (1a) inhibited the betacoronavirus SARS-CoV-2 and alphacoronavirus PEDV multiplication in Vero-E6 cells. As a result, Polycarpine (1a), a pan-inhibitor of Mpro, will function as an effective and promising antiviral option to combat CoVs infection and as a foundation for further therapeutic research.

Transcriptional level of inflammation markers associates with short-term brain structural changes in first-episode schizophrenia.

BACKGROUND: Inflammation has been implicated in the pathology of schizophrenia and may cause neuronal cell death and dendrite loss. Neuroimaging studies have highlighted longitudinal brain structural changes in patients with schizophrenia, yet it is unclear whether this is related to inflammation. We aim to address this question, by relating brain structural changes with the transcriptional profile of inflammation markers in the early stage of schizophrenia. METHODS: Thirty-eight patients with first-episode schizophrenia and 51 healthy controls were included. High-resolution T1-weighted magnetic resonance imaging (MRI) and clinical assessments were performed at baseline and 2 ~ 6 months follow-up for all subjects. Changes in the brain structure were analyzed using surface-based morphological analysis and correlated with the expression of immune cells-related gene sets of interest reported by previous reviews. Transcriptional data were retrieved from the Allen Human Brain Atlas. Furthermore, we examined the brain structural changes and peripheral inflammation markers in association with behavioral symptoms and cognitive functioning in patients. RESULTS: Patients exhibited accelerated cortical thickness decrease in the left frontal cortices, less decrease or an increase in the superior parietal lobule and right lateral occipital lobe, and increased volume in the bilateral pallidum, compared with controls. Changes in cortical thickness correlated with the transcriptional level of monocyte across cortical regions in patients (r = 0.54, p < 0.01), but not in controls (r = - 0.05, p = 0.76). In addition, cortical thickness change in the left superior parietal lobule positively correlated with changes in digital span-backward test scores in patients. CONCLUSIONS: Patients with schizophrenia exhibit regional-specific cortical thickness changes in the prefrontal and parietooccipital cortices, which is related to their cognitive impairment. Inflammation may be an important factor contributing to cortical thinning in first-episode schizophrenia. Our findings suggest that the immunity-brain-behavior association may play a crucial role in the pathogenesis of schizophrenia.

ß-Glycosylations with 2-Deoxy-2-(2,4-dinitrobenzenesulfonyl)-amino-glucosyl/galactosyl Selenoglycosides: Assembly of Partially N-Acetylated ß-(1 → 6)-Oligoglucosaminosides.

An efficient protocol has been established for ß-glycosylations with 2-deoxy-2-(2,4-dinitrobenzenesulfonyl)amino (2dDNsNH)-glucopyranosyl/galactopyranosyl selenoglycosides using PhSeCl/AgOTf as an activating system. The reaction features highly ß-selective glycosylation with a wide range of alcohol acceptors that are either sterically hindered or poorly nucleophilic. Thioglycoside- and selenoglycoside-based alcohols prove to be viable nucleophiles, opening up new opportunities for one-pot construction of oligosaccharides. The power of this approach is highlighted by the efficient assembly of tri-, hexa-, and nonasaccharides composed of ß-(1 → 6)-glucosaminosyl residues based on one-pot preparation of a triglucosaminosyl thioglycoside with DNs, phthaloyl, and 2,2,2-trichloroethoxycarbonyl as the protecting groups of amino groups. These glycans are potential antigens for developing glycoconjugate vaccines against microbial infections.

Synthesis, evaluation and molecular dynamics study of human toll-like receptor 2/6 specific monoacyl lipopeptides as candidate immunostimulants.

TLR2 agonists typified by the S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (Pam2CS) motif have exhibited powerful immunostimulatory activities. Based on simplified monoacyl lipopeptide (Carbamate-linked N-Ac PamCS), we describe interesting SAR investigations where modifications are done to alter the size of substituents on the cysteine amine, introduce ionizable groups to the terminal and insert aromatic substitutions to the aliphatic chain. Our structural modifications have led to a highly specific human TLR2/6 agonist 14a (EC50 = 0.424 nM), which behaves like Pam2CSK4 by inducing NF-κB activation to trigger downstream signaling pathways, such as subsequent phosphorylation of related proteins (p65, p38) and production of key inflammatory cytokines (IL-6, IL-1ß, TNF-α). Importantly, the ability to stimulate enhanced T cell response compared to Carbamate-linked N-Ac PamCS makes compound 14a a further potential candidate immunostimulant.

Magnetic Resonance Imaging throughout the Clinical Course of Schizophrenia: Neurobiological Underpinnings and Clinical Implications.

As a non-invasive detection method and an advanced imaging method, magnetic resonance imaging (MRI) has been widely used in the research of schizophrenia. Although a large number of neuroimaging studies have confirmed that MRI can display abnormal brain phenotypes in patients with schizophrenia, no valid uniform standard has been established for its clinical application. On the basis of previous evidence, we argue that MRI is an important tool throughout the whole clinical course of schizophrenia. The purpose of this commentary is to systematically describe the role of MRI in schizophrenia and to provide references for its clinical application.

Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides.

A mild and convenient method for the synthesis of reverse glycosyl fluorides (RGFs) has been developed that is based on the silver-promoted radical dehydroxymethylative fluorination of carbohydrates. A salient feature of the reaction is that furanoid and pyranoid carbohydrates furnish structurally diverse RGFs bearing a wide variety of functional groups in good to excellent yields. Intramolecular hydrogen atom transfer experiments revealed that the reaction involves an underexploited radical fluorination that proceeds via ß-fragmentation of sugar-derived primary alkoxyl radicals. Structurally divergent RGFs were obtained by catalytic C-F bond activation, and our method thus offers a concise and efficient strategy for the synthesis of reverse glycosides by late-stage diversification of RGFs. The potential of this method is showcased by the preparation and diversification of sotagliflozin, leading to the discovery of a promising SGLT2 inhibitor candidate.

A moderated chain mediation model examining the relation between smartphone addiction and intolerance of uncertainty among master's and PhD students.

The theories of relational regulation and compensatory Internet use suggest that intolerance of uncertainty influences smartphone addiction (SPA), which in turn is influenced by other aspects. This study used previous results to examine how intolerance of uncertainty affects SPA in PhD and master's degree programs. A convenience sample comprising 1727 master's and PhD students (99.9 %; 50.7 % female; Mage = 27.71; SD = 3.80; range = 21-43) was recruited. Using established questionnaires, we measured SPA, anxiety, positive coping style, perceived social support, and intolerance of uncertainty. The results demonstrated that intolerance of uncertainty positively affects SPA in terms of predictive power. Furthermore, anxiety and positive coping style mediate that link in a cascade fashion. A greater SPA indicates that the individual is less likely to use a positive coping style, has a higher anxiety level, and has a lower tolerance for uncertainty. While thinking about how intolerance of uncertainty affects anxiety and positive coping style, perceived social support mediates the relationship. Intolerance of uncertainty has less impact on anxiety and positive coping style when perceived social support is high. These results indicate the possibility of examining SPA prevention and intervention from several angles. Therefore, emotional regulation, which modifies anxiety and the tendency to use a positive coping style, may reduce the impact of intolerance of uncertainty on SPA. Another successful strategy for reducing smartphone addiction is to provide social support from loved ones and the community at large.

The Relationships between Effortful Control, Mind Wandering, and Mobile Phone Addiction Based on Network Analysis.

BACKGROUND: The prevailing mobile phone use brought the problem of addiction, which might cause negative consequences. Effortful control and mind wandering were associated with addictive behavior. The present study aimed to investigate the dimension-level relationships between effortful control, mind wandering, and mobile phone addiction. METHODS: A total of 1684 participants participated this study. The mobile phone addiction, effortful control, and mind wandering were measured through self-report scales, respectively. Dimension-level network of these psychological variables was estimated and bridge expected influence (BEI) values for each node was calculated. RESULTS: Dimensions of mobile phone addiction, effortful control, and mind wandering exhibited distinct and complex links to each other. The node "activation control" exhibited the highest negative BEI value (BEI = -0.32), whereas "spontaneous thinking" showed the highest positive BEI value (BEI = 0.20). CONCLUSIONS: Different dimensions of effortful control and mind wandering had varied yet significant connections with distinct dimensions of mobile phone addiction, facilitating understanding of the specific pathways underlying the three constructs. The identified dominant bridge nodes can provide potential targets for the intervention of mobile phone addiction.

Immune checkpoint inhibitors: breakthroughs in cancer treatment.

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.

Development of benzimidazole-based compounds as novel capsid assembly modulators for the treatment of HBV infection.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, the hit compound CDI (IC50 = 2.46 ± 0.33 µM) was identified by screening of an in-house compound library. And then novel potent benzimidazole derivatives were designed and synthesized as core assembly modulators, and their antiviral effects were evaluated in vitro and in vivo biological experiments. The results indicated that compound 26f displayed the most optimized modulator of HBV capsid assembly (IC50 = 0.51 ± 0.20 µM, EC50 = 2.24 ± 0.43 µM, CC50 = 84.29 µM) and high selectivity index. Moreover, treatment with compound 26f for 14 days significantly decreased serum levels of HBV DNA levels in the Hydrodynamic-Injection (HDI) mouse model. Therefore, compound 26f could be considered as a promising candidate drug for further development of novel HBV CAMs with the desired potency and safety.

Burnout and depression in college students.

Research on burnout has garnered considerable attention since its inception. However, the ongoing debate persists regarding the conceptual model of burnout and its relationship with depression. Thus, we conducted a network analysis to determine the dimensional structure of burnout and the burnout-depression overlap. The Maslach Burnout Inventory-Student Survey and Patient Health Questionnaire-9 were used to measure burnout and depression among 1096 college students. We constructed networks for burnout, depression, and a burnout-depression co-occurrence network. The results showed that cynicism symptom was the most central to the burnout network. In the co-occurrence network, depressive symptoms ("anhedonia", "fatigue") and burnout symptom ("doubting the significance of studies") were the most significant in causing burnout-depression comorbidity. Community detection revealed three communities within burnout symptoms, aligning closely with their three dimensions identified through factor analysis. Additionally, there was no overlap between burnout and depression. In conclusion, our findings support a multidimensional structure of burnout, affirming it as a distinct concept separate from depression. Cynicism, rather than exhaustion, plays the most important role in burnout and the burnout-depression comorbidity.

M6A-mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages.

Tumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non-coding RNA taurine-upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3-mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1-like macrophages in tumors, promoted the activation of CD8+ T cells through PD-L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD-L1 and CD47 expressions by acting as a sponge of miR-141 and miR-340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD-L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD-L1 and CD47 in HCC tissues. Moreover, the combination of Tug1-siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development.

How are patterned movements stored in working memory?

Introduction: In this study, the change detection paradigm was used to study the working memory of patterned movements and the relationship of this type of memory with the visuospatial sketchpad in three experiments. Methods: Experiment 1 measured participants' working memory capacity for patterned movements and explored the influence of stimulus type with indicators such as response time and accuracy rate. Experiments 2 and 3 explored the relationship between patterned movements and the visual and spatial subsystems, respectively. Results: The results of Experiment 1 indicated that individuals can store 3-4 patterned movements in working memory; however, a change in stimulus format or an increase in memory load may decrease the speed and efficiency of working memory processing. The results of Experiment 2 showed that working memory and visual working memory are independent when processing patterned movements. The results of Experiment 3 showed that the working memory of patterned movements was affected by spatial working memory. Discussion: Changes in stimulus type and memory load exerted different effects on the working memory capacity of participants. These results provide behavioral evidence that the storage of patterned movement information is independent of the visual subsystem but requires the spatial subsystem of the visuospatial sketchpad.

Comparative proteomic analysis of edible bird's nest from different origins.

Edible bird's nest (EBN) mainly made of saliva that secreted by a variety of swiftlets is a kind of precious traditional Chinese medicine. EBNs from different biological and geographical origins exhibit varieties in morphology, material composition, nutritive value and commercial value. Here, we collected four different EBN samples from Huaiji, China (Grass EBN), Nha Trang, Vietnam (Imperial EBN) and East Kalimantan, Indonesia (White EBN and Feather EBN) respectively, and applied label-free quantitative MS-based proteomics technique to identify its protein composition. First, phylogenetic analysis was performed based on cytb gene to identify its biological origin. Second, a total of 37 proteins of EBNs were identified, among which there were six common proteins that detected in all samples and exhibited relatively higher content. Gene ontology analysis revealed the possible function of EBN proteins, and principal component analysis and hierarchical clustering analysis based on 37 proteins were performed to compare the difference of various EBNs. In summary, our study deciphered the common and characteristic protein components of EBNs of different origins and described their possible functions by GO enrichment analysis, which helps to establish an objective and reliable quality evaluation system.

ZDHHC11 Suppresses Zika Virus Infections by Palmitoylating the Envelope Protein.

Zika virus (ZIKV) is an RNA-enveloped virus that belongs to the Flavivirus genus, and ZIKV infections potentially induce severe neurodegenerative diseases and impair male fertility. Palmitoylation is an important post-translational modification of proteins that is mediated by a series of DHHC-palmitoyl transferases, which are implicated in various biological processes and viral infections. However, it remains to be investigated whether palmitoylation regulates ZIKV infections. In this study, we initially observed that the inhibition of palmitoylation by 2-bromopalmitate (2-BP) enhanced ZIKV infections, and determined that the envelope protein of ZIKV is palmitoylated at Cys308. ZDHHC11 was identified as the predominant enzyme that interacts with the ZIKV envelope protein and catalyzes its palmitoylation. Notably, ZDHHC11 suppressed ZIKV infections in an enzymatic activity-dependent manner and ZDHHC11 knockdown promoted ZIKV infection. In conclusion, we proposed that the envelope protein of ZIKV undergoes a novel post-translational modification and identified a distinct mechanism in which ZDHHC11 suppresses ZIKV infections via palmitoylation of the ZIKV envelope protein.

Design and preparation of stress-free epitaxial BaTiO3 polydomain films by RF magnetron sputtering.

Domain structures of BaTiO3 thick films grown on (100) SrTiO3 single-crystal substrates were engineered using an RF magnetron sputtering deposition process. By tuning the sputtering power and cooling rate and using an off-axis sputtering technique to prepare conducting perovskite oxide bottom electrode with heteroepitaxial quality, we have deposited epitaxial tetragonal single-domain and polydomain BaTiO3 films with a self-assembled three-domain architecture. The electrical properties and microstructure of the BaTiO3 films were characterized, and a c/a1/a2 cellular polydomain structure was clearly observed in as-grown films by optical microscopy. Such a polydomain structure was a consequence of a complete relaxation of misfit stresses of the film. Engineering of this self-assembled microstructure has great potential in providing large, field-tunable pyroelectric and electromechanical responses in next-generation microelectronic devices and micro-electro-mechanical systems (MEMS).

Recent Studies on the Pharmacological Activities and Structural Modifications of Compound-K.

Ginsenosides, the essential active ingredients extracted from ginseng, have been well studied in the past several decades because of their numerous pharmacological properties including anti-tumor, anti-inflammatory, and anti-diabetic activities, as well as hepatoprotection, skin protection, and memory improvement, etc. Compound-K (CK) is the major metabolite derived from the deglycosylation of ginsenosides by intestinal bacteria and has been proved to be the actual active entity absorbed into the systemic circulation. In this review, we comprehensively elucidate the pharmacological activities of CK from the molecular mechanism, as well as its structurally modified derivatives. We hope this review would be helpful to get a systematic summary and provide constructive insights for the further research of CK.

Modified Baihu decoction therapeutically remodels gut microbiota to inhibit acute gouty arthritis.

Background: Acute gouty arthritis (AGA) is the most common first symptom of gout, and the development of gout as a metabolic and immune inflammatory disease is also correlated with the gut microbiota. However, the mechanism of the effect of changes in the gut microbiota on AGA remains unclear. The intestinal flora can not only affect purine metabolism or regulate inflammation, but also influence the therapeutic effect of drugs on AGA. The aim of this study was to investigate the exact mechanism of modified Baihu decoction (MBD) in the treatment of AGA and whether it is related to the regulation of the structure of the intestinal flora. Methods: On the 21st day of MBD administration by continuous gavage, a rat acute gouty arthritis model was constructed using sodium urate (0.1 mL/rat, 50 mg/mL), and the ankle joint swelling was measured before and 4 h, 8 h, 24 h, and 48 h after the injection of sodium urate. After 48 h of sodium urate injection, serum, liver, kidney, ankle synovial tissue and feces were collected from rats. The collected samples were examined and analyzed using H&E, Elisa, Immunohistochemistry, Histopathology, 16S rDNA, and Biochemical analysis. To investigate the mechanism of MBD to alleviate AGA using pro-inflammatory factors and intestinal flora. Results: MBD (5.84, 35 g/kg) was administered orally to AGA rats and diclofenac sodium tablets (DS-tablets) were used as standard treatment control. Serum biochemical assessment confirmed that MBD is a safe drug for the treatment of AGA. In addition, our findings confirmed that MBD relieved AGA-related symptoms, such as toe swelling. Lowering serum levels of uric acid, IL-1ß, and TGF-ß1 immunohistochemical results also confirmed that MBD reduced the expression of inflammatory elements such as IL-1ß, NLRP3, ASC, and Caspase-1 in synovial tissue.Furthermore, compared with control group, the 16s rDNA sequencing of AGA rat faeces revealed an increase in the relative abundance of Lachnospiraceae, Muribaculaceae, and Bifidobacteriaceae species. While the relative abundance of Lactobacillaceae, Erysipelotrichaceae, Ruminococcaceae, Prevotellaceae and Enterobacteriaceae showed a relative decrease in species abundance. Of these, the reduction in species abundance of Enterobacteriaceae was associated with a reduction in amino acid metabolism and environmental perception. After MBD therapeutic intervention, the disturbance of the intestinal flora caused by AGA was restored. Conclusion: In summary, MBD is an effective agent for the treatment of AGA, with the potential mechanism being the regulation of intestinal flora to control inflammation. This would help to promote the therapeutic effect of MBD on AGA.