Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis.

BACKGROUND: Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H+-ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD+ (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase. METHODS: Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [3H]chloroquine (endosomal pH), and [14C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V1G1/V0d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload. RESULTS: NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions. CONCLUSION: NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.

Mycoplasma invasion into host cells: An integrated model of infection strategy.

Mycoplasma belong to the genus Mollicutes and are notable for their small genome sizes (500-1300 kb) and limited biosynthetic capabilities. They exhibit pathogenicity by invading various cell types to survive as intracellular pathogens. Adhesion is a crucial prerequisite for successful invasion and is orchestrated by the interplay between mycoplasma surface adhesins and specific receptors on the host cell membrane. Invasion relies heavily on clathrin- and caveolae-mediated internalization, accompanied by multiple activated kinases, cytoskeletal rearrangement, and a myriad of morphological alterations, such as membrane invagination, nuclear hypertrophy and aggregation, cytoplasmic edema, and vacuolization. Once mycoplasma successfully invade host cells, they establish resilient sanctuaries in vesicles, cytoplasm, perinuclear regions, and the nucleus, wherein specific environmental conditions favor long-term survival. Although lysosomal degradation and autophagy can eliminate most invading mycoplasmas, some viable bacteria can be released into the extracellular environment via exocytosis, a crucial factor in the prolonging infection persistence. This review explores the intricate mechanisms by which mycoplasma invades host cells and perpetuates their elusive survival, with the aim of highlighting the challenge of eradicating this enigmatic bacterium.

Interplay of miRNAs and molecular pathways in spaceflight-induced depression: Insights from a rat model using simulated complex space environment.

Depression is a significant concern among astronauts, yet the molecular mechanisms underlying spaceflight-induced depression remain poorly understood. MicroRNAs (miRNAs) have emerged as potential regulators of neuropsychiatric disorders, including depression, but their specific role in space-induced depression remains unexplored. This study aimed to elucidate the involvement of candidate miRNAs (miR-455-3p, miR-206-3p, miR-132-3p, miR-16-5p, miR-124-3p, and miR-145-3p) and their interaction with differentially expressed genes (DEGs) in the neurobiology of spaceflight-induced depressive behavior. Using a simulated space environmental model (SCSE) for 21 days, depressive behavior was induced in rats, and candidate miRNA expressions and DEGs in the cortex region were analyzed through qRT-PCR and HPLC, respectively. Results showed that SCSE-exposed rats exhibited depressive behaviors, including anhedonia, increased immobility, and anxiousness compared to controls. Further analysis revealed increased hydrogen peroxide levels and decreased superoxide dismutase levels in the SCSE group, indicating abnormal oxidative stress in the cerebral cortex. Moreover, miRNA analysis demonstrated significant upregulation of miR-455-3p, miR-206-3p, miR-132-3p, and miR-16-5p expression. Among the DEGs identified, the in silico analysis highlighted their involvement in crucial pathways such as glutamatergic signaling, GABA synaptic pathway, and calcium signaling, implicating their role in spaceflight-induced depression. Protein-protein interaction analysis identified hub genes, including DLG4, DLG3, GRIN1, GRIN2B, GRIN2A, SYNGAP1, DLGAP1, GRIK2, and GRIN3A, impacting neuronal dysfunction functions in the cortex region of SCSE depressive rats. DLG4 emerged as a core gene regulated by miR-455-3p and miR-206-3p. Overall, this study underscores the potential of miRNAs as biomarkers for mood disorders and neurological abnormalities associated with spaceflight, advancing health sciences, and space health care.

Treponema pallidum lipoprotein Tp0768 promotes the migration and adhesion of THP-1 cells to vascular endothelial cells through stress of the endoplasmic reticulum and the NF-κB/HIF-1α pathway.

Endothelial cell injury is a key factor in the spread of infection and pathogenicity of Treponema pallidum. The migration and adhesion reaction mediated by T. pallidum lipoprotein plays an important role. This study aimed to systematically explore the migration and adhesion effect of T. pallidum lipoprotein Tp0768 and its molecular mechanism. Stimulating vascular endothelial cells with Tp0768 increased the expression of ICAM-1, MCP-1, and IL-8. Moreover, it promoted the migration and adhesion of THP-1 cells to vascular endothelial cells. Our results revealed that Tp0768 promoted the THP-1 cells migrating and adhering to vascular endothelial cells by the PERK and IRE-1α pathways of endoplasmic reticulum (ER) stress. We further demonstrated that the inhibition of the NF-κB pathway and the downregulation of hypoxia-inducible factor 1 alpha (HIF-1α) reduced the mRNA levels of ICAM-1, MCP-1, and IL-8 induced by Tp0768. Also, the adhesion rate of THP-1 cells to endothelial cells decreased. After inhibiting ER stress, NF-κB p65 nuclear translocation was weakened, and the mRNA level of HIF-1α was also significantly downregulated. Our results indicated that T. pallidum lipoprotein Tp0768 promoted the migration and adhesion of THP-1 cells to vascular endothelial cells through ER stress and NF-κB/HIF-1α pathway.

Beyond Conventional Enhancements: Self-Organization of a Buffer Material on Tin Oxide as a Game-Changer for Improving the Performance of Inverted Organic Solar Cells.

Inverted organic solar cells (OSCs) have garnered significant interest due to their remarkable stability. In this study, the efficiency and stability of inverted OSCs are enhanced via the in situ self-organization (SO) of an interfacial modification material Phen-NaDPO onto tin oxide (SnO2). During the device fabrication, Phen-NaDPO is spin-coated with the active materials all together on SnO2. Driven by the interactions with SnO2 and the thermodynamic forces due to its high surface energy and the convection flow, Phen-NaDPO spontaneously migrates to the SnO2 interface, resulting in the formation of an in situ modification layer on SnO2. This self-organization of Phen-NaDPO not only effectively reduces the work function of SnO2, but also enhances the ordered molecular stacking and manipulates the vertical morphology of the active layer, which suppress the surface trap-assisted recombination and minimize the charge extraction. As a result, the SO devices based on PM6:Y6 exhibit significantly improved photovoltaic performance with an enhanced power conversion efficiency of 17.62%. Moreover, the stability of the SO device is also improved. Furthermore, the SO ternary devices based on PM6:D18:L8-BO achieved an impressive PCE of 18.87%, standing as one of the highest values for single-junction inverted organic solar cells to date.

Molecular mechanisms of aging and anti-aging strategies.

Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.

Computer-aided designing of a novel multi­epitope DNA vaccine against severe fever with thrombocytopenia syndrome virus.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (Dabie bandavirus), which has become a substantial risk to public health. No specific treatment is available now, that calls for an effective vaccine. Given this, we aimed to develop a multi-epitope DNA vaccine through the help of bioinformatics. The final DNA vaccine was inserted into a special plasmid vector pVAX1, consisting of CD8+ T cell epitopes, CD4+ T cell epitopes and B cell epitopes (six epitopes each) screened from four genome-encoded proteins--nuclear protein (NP), glycoprotein (GP), RNA-dependent RNA polymerase (RdRp), as well as nonstructural protein (NSs). To ascertain if the predicted structure would be stable and successful in preventing infection, an immunological simulation was run on it. In conclusion, we designed a multi-epitope DNA vaccine that is expected to be effective against Dabie bandavirus, but in vivo trials are needed to verify this claim.

Joint association of cardiovascular health and frailty with all-cause and cause-specific mortality: a prospective study.

BACKGROUND: Poor cardiovascular health (CVH) and physical frailty were reported to increase mortality risk, but their joint effects have not been fully elucidated. OBJECTIVES: We aimed to explore the separate and joint effects of CVH and frailty on mortality based on two perspectives of Life's Essential 8 (LE8) and Framingham Risk Score (FRS). METHODS: 21 062 participants in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018 were involved in this study. CVH was evaluated by the LE8 and FRS, and categorized into low, moderate and high CVH groups. Cox proportional hazard models were applied to estimate the separate and joint associations of CVH and frailty index (FI) with all-cause, cardiovascular disease (CVD) and cancer mortality. RESULTS: Over a median follow-up period of 87 months (95% CI: 86.0-88.0), 2036 deaths occurred. The separate linear dose-response relationships between CVH, frailty and mortality were observed (nonlinear P > .05). The combination of low CVH/frailty was negatively associated with all-cause mortality [hazard ratio (HR) and 95%CI: low LE8*FI, 5.30 (3.74, 7.52); high FRS*FI, 4.34 (3.20, 5.88)], CVD mortality [low LE8*FI, 6.57 (3.54, 12.22); high FRS*FI, 7.29 (3.92, 13.55)] and cancer mortality [low LE8*FI, 1.99 (1.14, 3.25); high FRS*FI, 2.32 (1.30, 4.15)], with high CVH/fit group as reference. Further stratified analyses showed that the combined burden of mortality from frailty and low CVH was greater among the young and females. CONCLUSIONS: Low CVH and frailty were independently and jointly correlated with greater risk of all-cause, CVD and cancer deaths, especially among the young and females.

Microbial creation of ß-Nicotinamide mononucleotide and its regulation of lipid metabolism in the liver of high-fat diet mice.

ß-Nicotinamide mononucleotide (NMN) is a biologically active nucleotide that regulates the physiological metabolism of the body by rapidly increasing nicotinamide adenine dinucleotide (NAD+). To determine the safety and biological activity of NMN resources, we constructed a recombinant strain of P. pastoris that heterologously expresses nicotinamide-phosphate ribosyltransferase (NAMPT), and subsequently catalyzed and purified the expressed product to obtain NMN. Consequently, this study established a high-fat diet (HFD) obese model to investigate the lipid-lowering activity of NMN. The findings showed that NMN supplementation directly increased the NAD+ levels, and reduced HFD-induced liver injury and lipid deposition. NMN treatment significantly decreased total cholesterol (TC) and triglyceride (TG) in serum and liver, as well as alanine aminotransferase (ALT) and insulin levels in serum (p < .05 or p < .01). In conclusion, this study combined synthetic biology with nutritional evaluation to confirm that P. pastoris-generated NMN modulated lipid metabolism in HFD mice, offering a theoretical framework and evidence for the application of microbially created NMN.

Linking abnormal fat distribution with HFpEF and diastolic dysfunction: a systematic review, meta-analysis, and meta-regression of observational studies.

BACKGROUND: The global prevalence of obesity has escalated into a formidable health challenge intricately linked with the risk of developing cardiac diastolic disfunction and heart failure with preserved ejection fraction (HFpEF). Abnormal fat distribution is potentially strongly associated with an increased risk of cardiac diastolic dysfunction, and we aimed to scrutinize and elucidate the correlation between them. METHODS: Following the Cochrane Handbook and PRISMA 2020 guidelines, we systematically reviewed the literature from PubMed, Embase, and Web of Science. We focused on studies reporting the mean and standard deviation (SD) of abnormal fat in HFpEF or cardiac diastolic dysfunction patients and the Pearson/Spearman correlation coefficients for the relationship between abnormal fat distribution and the risk of developing cardiac diastolic dysfunction. Data were standardized to the standard mean difference (SMD) and Fisher's z value for meta-analysis. RESULTS: After progressive filtering and selection, 63 studies (43,113 participants) were included in the quantitative analyses. Abnormal fat distribution was significantly greater in participants with cardiac diastolic dysfunction than in controls [SMD 0.88 (0.69, 1.08)], especially in epicardial adipose tissue [SMD 0.99 (0.73, 1.25)]. Abnormal fat distribution was significantly correlated with the risk of developing cardiac diastolic dysfunction [E/E': 0.23 (0.18, 0.27), global longitudinal strain: r=-0.11 (-0.24, 0.02)]. Meta-regression revealed sample size as a potential heterogeneous source, and subgroup analyses revealed a stronger association between abnormal fat distribution and the risk of developing cardiac diastolic dysfunction in the overweight and obese population. CONCLUSION: Abnormal fat distribution was significantly associated with the risk of developing cardiac diastolic dysfunction. TRIAL REGISTRATION: CRD42024543774.

Causal Associations Between Tea Consumption and REM Sleep Behavior Disorder: A Mendelian Randomization Study.

BACKGROUND: Previous studies have shown that tea consumption may have a protective effect against neurodegenerative diseases. However, the exact causal relationship between tea consumption and the precursor stages of certain neurodegenerative diseases, namely REM sleep behavior disorder (RBD), remains unclear. To evaluate the causal association between tea consumption and RBD, we employed a Mendelian randomization study. METHODS: We identified genetic instrumental variables that are significantly associated with tea consumption through genome-wide association studies (GWAS) in European populations. Bidirectional two-sample Mendelian randomization was utilized to determine the causal relationship between tea consumption and RBD, while sensitivity analyses were further employed to evaluate the robustness of the results. The multivariate Mendelian randomization method was used to assess the influence of relevant confounding factors on the results. RESULTS: In the MR analysis using the inverse variance weighting method, a significant causal relationship between tea consumption and RBD was observed (OR=0.046, 95% CI 0.004-0.563, p=0.016). The consistency of findings across maximum likelihood, MR PRESSO, and multivariate MR after adjusting for potential confounding further supports this causal association. Sensitivity analyses revealed no evidence of heterogeneity or pleiotropy. CONCLUSIONS: The findings of our study demonstrate a robust causal association between tea consumption and RBD, indicating that tea consumption may serve as a protective factor against the development of RBD.

Study on the role of CCM3 gene and lead exposure induced neurotoxicity through neurovascular units.

This study aimed to determine the toxic effects of vascular CCM3 gene deficiency and lead (Pb) exposure on the nervous system. Lentiviral transfection was performed to generate a stable strain of brain microvascular endothelial cells with low CCM3 expression. MTT assay assessed the survival rate of cells exposed to Pb, determining the dose and duration of Pb exposure in vitro. Proteomic analysis was performed on the differentially expressed proteins in bEnd3 and HT22 cells and flow cytometry was used to detect cell apoptosis. Finally, urine samples from pregnant and postpartum women were subjected to ICP-MS to detect Pb levels and HPLC to detect neurotransmitter metabolites. Based on the proteomic analysis of bEnd3 (CCM3-/-) cells co-cultured with HT22 cells, it was determined that HT22 cells and CCM3 genes interfered with bEnd3 cell differential proteins,2 including apoptosis and ferroptosis pathways. Electron microscopy observation, ICP-MS iron ion loading detection, and WB determination of protein GPX4 expression confirmed that HT22 cells undergo apoptosis, while bEnd3 cells undergo multiple pathways of iron death and apoptosis regulation. Furthermore, a linear regression model showed the interaction between maternal urine Pb levels, the rs9818496 site of the CCM3 SNP in peripheral blood DNA, and the concentration of the neurotransmitter metabolite 5-HIAA in maternal urine (F=4.198, P < 0.05). bEnd3 cells with CCM3 gene deficiency can induce HT22 cell apoptosis through iron death and apoptosis pathways under Pb exposure in a combined cell culture Pb exposure model, and CCM3 gene deficiency in endothelial cells and Pb exposure interacts with neural cell HT22. Epidemiological studies on maternal and newborn infants further confirmed the interaction between urine Pb levels in mothers and the SNP rs9818496 site of the CCM3 gene in peripheral blood DNA.

Photodynamic inactivation of edible photosensitizers for fresh food preservation: Comprehensive mechanism of action and enhancement strategies.

Foodborne harmful bacteria not only cause waste of fresh food, but also pose a major threat to human health. Among many new sterilization and preservation technologies, photodynamic inactivation (PDI) has the advantages of low-cost, broad-spectrum, energy-saving, nontoxic, and high efficiency. In particular, PDI based on edible photosensitizers (PSs) has a broader application prospect due to edible, accessible, and renewable features, it also can maximize the retention of the nutritional characteristics and sensory quality of the food. Therefore, it is meaningful and necessary to review edible PSs and edible PSs-mediated PDI, which can help to arouse interest and concern and promote the further development of edible PSs-mediated PDI in the future field of nonthermally sterilized food preservation. Herein, the classification and modification of edible PSs, PS-mediated in vivo and PS-mediated in vitro mechanism of PDI, strengthening strategy to improve PDI efficiency by the structure change synergistic and multitechnical means, as well as the application in fresh food preservation were reviewed systematically. Finally, the deficiency and possible future perspectives of edible PSs-mediated PDI were articulated. This review aimed to provide new perspective for the future food preservation and microbial control.

Paeoniflorin loaded liposomes modified with glycyrrhetinic acid for liver-targeting: preparation, characterization, and pharmacokinetic study.

OBJECTIVE: To enhance the retention times and therapeutic efficacy of paeoniflorin (PF), a liver-targeted drug delivery system has been developed using glycyrrhetinic acid (GA) as a ligand. SIGNIFICANCE: The development and optimization of GA-modified PF liposomes (GPLs) have shown promising potential for targeted delivery to the liver, opening up new possibilities for liver disease treatment. METHODS: This study aimed to identify the best prescriptions using single-factor experiments and response surface methodology. The formulation morphology was determined using transmission electron microscopy. Tissue distribution was observed through in vivo imaging, and pharmacokinetic studies were conducted. RESULTS: The results indicated that GPLs, prepared using the thin film dispersion method and response surface optimization, exhibited well-dispersed and uniformly sized particles. The in vitro release rate of GPLs was slower compared to PF monomers, suggesting a sustained release effect. The liver-targeting ability of GA resulted in stronger fluorescence signals in the liver for targeted liposomes compared to non-targeted liposomes. Furthermore, pharmacokinetic studies demonstrated that GPLs significantly prolonged the residence time of PF in the bloodstream, thereby contributing to prolonged efficacy. CONCLUSION: These findings suggest that GPLs are more effective than PF monomers in terms of controlling drug release and delivering drugs to specific targets, highlighting the potential of PF as a liver-protective drug.

Construction and validation of a nomogram for predicting fear of falling related activity restrictions in community-dwelling older adults.

Fear of falling related activity restrictions are widespread among older adults, leading to several adverse effects. Given these consequences, there is an urgent need for a comprehensive assessment tool that integrates various risk factors to predict the likelihood of older adults experiencing such activity restrictions. This cross-sectional study investigated fear of falling related activity restrictions and its influencing factors, simultaneously constructed and validated a nomogram among older adults residing in the communities in China. The model includes variables like age, gender, self-rated health, past year injurious falls, gait stability, anxiety, and cognitive impairment. It showed an AUC of 0.892. Internal validation had an AUC of 0.893, and external validation had an AUC of 0.939. Calibration curve showed good fit, and decision curve showed high clinical benefits. It's an intuitive tool for medical professionals to identify older adults at high risk of activity restrictions due to fear of falling.

Revealing the Influence of Electron Migration Inside Polymer Electrolyte on Li+ Transport and Interphase Reconfiguration for Li Metal Batteries.

The development of highly producible and interfacial compatible in situ polymerized electrolytes for solid-state lithium metal batteries (SSLMBs) have been plagued by insufficient transport kinetics and uncontrollable dendrite propagation. Herein, we seek to explore a rationally designed nanofiber architecture to balance all the criteria of SSLMBs, in which La0.6Sr0.4CoO3-δ (LSC) enriched with high valence-state Co species and oxygen vacancies is developed as electronically conductive nanofillers embedded within ZnO/Zn3N2-functionalized polyimide (Zn-PI) nanofiber framework for the first time, to establish Li+ transport highways for poly vinylene carbonate (PVC) electrolyte and eliminate nonuniform Li deposits. Revealed by characterization and theoretical calculation under electric field, the positive-negative electrical dipole layer in LSC derived from electron migration between Co and O atoms aids in accelerating Li+ diffusion kinetics through densified electric field around filler particle, featuring a remarkable ionic conductivity of 1.50 mS cm-1 at 25 °C and a high Li+ transference number of 0.91 without the risk of electron leakage. Integrating with the preferential sacrifice of ZnO/Zn3N2 on PI nanofiber upon immediate detection of dendritic Li, which takes part in reconfiguring hierarchical SEI chemistry dominated by LixNy/Li-Zn alloy inner layer and LiF outer layer, SSLMBs are further endowed with prolonged cycling lifespan and exceptional rate capability.

In Situ Constructing Robust and Highly Conductive Solid Electrolyte with Tailored Interfacial Chemistry for Durable Li Metal Batteries.

Employing nanofiber framework for in situ polymerized solid-state lithium metal batteries (SSLMBs) is impeded by the insufficient Li+ transport properties and severe dendritic Li growth. Both critical issues originate from the shortage of Li+ conduction highways and nonuniform Li+ flux, as randomly-scattered nanofiber backbone is highly prone to slippage during battery assembly. Herein, a robust fabric of Li0.33 La0.56 Ce0.06 Ti0.94 O3-δ /polyacrylonitrile framework (p-LLCTO/PAN) with inbuilt Li+ transport channels and high interfacial Li+ flux is reported to manipulate the critical current density of SSLMBs. Upon the merits of defective LLCTO fillers, TFSI- confinement and linear alignment of Li+ conduction pathways are realized inside 1D p-LLCTO/PAN tunnels, enabling remarkable ionic conductivity of 1.21 mS cm-1 (26 °C) and tLi+ of 0.93 for in situ polymerized polyvinylene carbonate (PVC) electrolyte. Specifically, molecular reinforcement protocol on PAN framework further rearranges the Li+ highway distribution on Li metal and alters Li dendrite nucleation pattern, boosting a homogeneous Li deposition behavior with favorable SEI interface chemistry. Accordingly, excellent capacity retention of 76.7% over 1000 cycles at 2 C for Li||LiFePO4 battery and 76.2% over 500 cycles at 1 C for Li||LiNi0.5 Co0.2 Mn0.3 O2 battery are delivered by p-LLCTO/PAN/PVC electrolyte, presenting feasible route in overcoming the bottleneck of dendrite penetration in in situ polymerized SSLMBs.

HBV covalently closed circular DNA minichromosomes in distinct epigenetic transcriptional states differ in their vulnerability to damage.

BACKGROUND AND AIMS: HBV covalently closed circular DNA (cccDNA) is a major obstacle for a cure of chronic hepatitis B. Accumulating evidence suggests that epigenetic modifications regulate the transcriptional activity of cccDNA minichromosomes. However, it remains unclear how the epigenetic state of cccDNA affects its stability. APPROACHES AND RESULTS: By using HBV infection cell models and in vitro and in vivo recombinant cccDNA (rcccDNA) and HBVcircle models, the reduction rate of HBV cccDNA and the efficacy of apolipoprotein B mRNA editing enzyme catalytic subunit 3A (APOBEC3A)-mediated and CRISPR/CRISPR-associated 9 (Cas9)-mediated cccDNA targeting were compared between cccDNAs with distinct transcriptional activities. Interferon-α treatment and hepatitis B x protein (HBx) deletion were applied as two strategies for cccDNA repression. Chromatin immunoprecipitation and micrococcal nuclease assays were performed to determine the epigenetic pattern of cccDNA. HBV cccDNA levels remained stable in nondividing hepatocytes; however, they were significantly reduced during cell division, and the reduction rate was similar between cccDNAs in transcriptionally active and transcriptionally repressed states. Strikingly, HBV rcccDNA without HBx expression exhibited a significantly longer persistence in mice. The cccDNA with low transcriptional activity exhibited an epigenetically inactive pattern and was more difficult to access by APOBEC3A and engineered CRISPR-Cas9. The epigenetic regulator activating cccDNA increased its vulnerability to APOBEC3A. CONCLUSIONS: HBV cccDNA minichromosomes in distinct epigenetic transcriptional states showed a similar reduction rate during cell division but significantly differed in their accessibility and vulnerability to targeted nucleases and antiviral agents. Epigenetic sensitization of cccDNA makes it more susceptible to damage and may potentially contribute to an HBV cure.

Investigation of the immune escape mechanism of Treponema pallidum.

BACKGROUND: Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subspecies pallidum (T. pallidum), which is a public health problem that seriously affects human health worldwide. T. pallidum is characterized by early transmission and immune escape and is therefore termed an "invisible pathogen". METHODS: This review systematically summarizes the host's innate and adaptive immune responses to T. pallidum infection as well as the escape mechanisms of T. pallidum. PURPOSE: To lay the foundation for assessing the pathogenic mechanism and the systematic prevention and treatment of syphilis. CONCLUSION: The immune escape mechanism of T. pallidum plays an important role in its survival. Exploring the occurrence and development of these mechanisms has laid the foundation for the development of syphilis vaccine.

TLR2 mediates autophagy through ERK signaling pathway in Chlamydia psittaci CPSIT_p7 protein-stimulated RAW264.7 cells.

Chlamydia psittaci is a zoonotic pathogen found in birds and humans. Macrophages, major components of the innate immune system, can resist chlamydial infections and trigger adaptive immune responses. However, the molecular mechanisms underlying the action of macrophages against C. psittaci infection are not well understood. This study investigated the roles and mechanisms of plasmid-encoded protein CPSIT_p7 of C. psittaci in regulating autophagy in RAW264.7 cells. The results demonstrated that stimulation of RAW264.7 with C. psittaci plasmid protein CPSIT_p7 induced the expressions of the autophagy signaling primary regulators LC3 and Beclin1, which could also significantly induce the phosphorylation levels of ERK, JNK, p38, and Akt. Next, siRNA knockdown of TLR2 resulted in significant downregulation of CPSIT_p7-triggered autophagy in RAW264.7 cells. Moreover, the extracellular regulated protein kinase (ERK) inhibitor PD98059 markedly reduced autophagy in CPSIT_p7-stimulated macrophages. In summary, these results indicated that TLR2 plays an essential role in the induction of autophagy through the ERK signaling pathway in CPSIT_p7-stimulated RAW264.7 cells.