Inhibition of the RLR signaling pathway by SARS-CoV-2 ORF7b is mediated by MAVS and abrogated by ORF7b-homologous interfering peptide.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and characterized by dysregulated immune response. Studies have shown that the SARS-CoV-2 accessory protein ORF7b induces host cell apoptosis through the tumor necrosis factor alpha (TNF-α) pathway and blocks the production of interferon beta (IFN-ß). The underlying mechanism remains to be investigated. In this study, we found that ORF7b facilitated viral infection and production, and inhibited the RIG-I-like receptor (RLR) signaling pathway through selectively interacting with mitochondrial antiviral-signaling protein (MAVS). MAVS439-466 region and MAVS Lys461 were essential for the physical association between MAVS and ORF7b, and the inhibition of the RLR signaling pathway by ORF7b. MAVSK461/K63 ubiquitination was essential for the RLR signaling regulated by the MAVS-ORF7b complex. ORF7b interfered with the recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) and the activation of the RLR signaling pathway by MAVS. Furthermore, interfering peptides targeting the ORF7b complex reversed the ORF7b-suppressed MAVS-RLR signaling pathway. The most potent interfering peptide V disrupts the formation of ORF7b tetramers, reverses the levels of the ORF7b-inhibited physical association between MAVS and TRAF6, leading to the suppression of viral growth and infection. Overall, this study provides a mechanism for the suppression of innate immunity by SARS-CoV-2 infection and the mechanism-based approach via interfering peptides to potentially prevent SARS-CoV-2 infection.IMPORTANCEThe pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and continues to be a threat to public health. It is imperative to understand the biology of SARS-CoV-2 infection and find approaches to prevent SARS-CoV-2 infection and ameliorate COVID-19. Multiple SARS-CoV-2 proteins are known to function on the innate immune response, but the underlying mechanism remains unknown. This study shows that ORF7b inhibits the RIG-I-like receptor (RLR) signaling pathway through the physical association between ORF7b and mitochondrial antiviral-signaling protein (MAVS), impairing the K63-linked MAVS polyubiquitination and its recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) to MAVS. The most potent interfering peptide V targeting the ORF7b-MAVS complex may reverse the suppression of the MAVS-mediated RLR signaling pathway by ORF7b and prevent viral infection and production. This study may provide new insights into the pathogenic mechanism of SARS-CoV-2 and a strategy to develop new drugs to prevent SARS-CoV-2 infection.

LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive. METHODS: Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell-specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl2; 0.5 mol/L; 42 days). RESULTS: Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl2-treated mice. Global or vascular smooth muscle cell-specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II- and CaCl2-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process. CONCLUSIONS: Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.

The CDE region of feline Calicivirus VP1 protein is a potential candidate subunit vaccine.

BACKGROUND: Feline calicivirus (FCV) infection causes severe upper respiratory disease in cats, but there are no effective vaccines available for preventing FCV infection. Subunit vaccines have the advantages of safety, low cost and excellent immunogenicity, but no FCV subunit vaccine is currently available. The CDE protein is the dominant neutralizing epitope region of the main antigenic structural protein of FCV, VP1. Therefore, this study evaluated the effectiveness of the CDE region as a truncated FCV VP1 protein in preventing FCV infection to provide a strategy for developing potential FCV subunit vaccines. RESULTS: Through the prediction of FCV VP1 epitopes, we found that the E region is the dominant neutralizing epitope region. By analysing the spatial structure of VP1 protein, 13 amino acid sites in the CD and E regions were found to form hydrogen bonding interactions. The results show the presence of these interaction forces supports the E region, helping improve the stability and expression level of the soluble E protein. Therefore, we selected the CDE protein as the immunogen for the immunization of felines. After immunization with the CDE protein, we found significant stimulation of IgG, IgA and neutralizing antibody production in serum and swab samples, and the cytokine TNF-α levels and the numbers of CD4+ T lymphocytes were increased. Moreover, a viral challenge trial indicated that the protection generated by the CDE subunit vaccine significantly reduced the incidence of disease in animals. CONCLUSIONS: For the first time, we studied the efficacy of the CDE protein, which is the dominant neutralizing epitope region of the FCV VP1 protein, in preventing FCV infection. We revealed that the CDE protein can significantly activate humoral, mucosal and cellular immunity, and the resulting protective effect can significantly reduce the incidence of animal disease. The CDE region of the FCV capsid is easy to produce and has high stability and excellent immunogenicity, which makes it a candidate for low-cost vaccines.

Development and validation of a nomogram to predict the risk of sepsis-associated encephalopathy for septic patients in PICU: a multicenter retrospective cohort study.

BACKGROUND: Patients with sepsis-associated encephalopathy (SAE) have higher mortality rates and longer ICU stays. Predictors of SAE are yet to be identified. We aimed to establish an effective and simple-to-use nomogram for the individual prediction of SAE in patients with sepsis admitted to pediatric intensive care unit (PICU) in order to prevent early onset of SAE. METHODS: In this retrospective multicenter study, we screened 790 patients with sepsis admitted to the PICU of three hospitals in Shandong, China. Least absolute shrinkage and selection operator regression was used for variable selection and regularization in the training cohort. The selected variables were used to construct a nomogram to predict the risk of SAE in patients with sepsis in the PICU. The nomogram performance was assessed using discrimination and calibration. RESULTS: From January 2017 to May 2022, 613 patients with sepsis from three centers were eligible for inclusion in the final study. The training cohort consisted of 251 patients, and the two independent validation cohorts consisted of 193 and 169 patients. Overall, 237 (38.7%) patients developed SAE. The morbidity of SAE in patients with sepsis is associated with the respiratory rate, blood urea nitrogen, activated partial thromboplastin time, arterial partial pressure of carbon dioxide, and pediatric critical illness score. We generated a nomogram for the early identification of SAE in the training cohort (area under curve [AUC] 0.82, 95% confidence interval [CI] 0.76-0.88, sensitivity 65.6%, specificity 88.8%) and validation cohort (validation cohort 1: AUC 0.80, 95% CI 0.74-0.86, sensitivity 75.0%, specificity 74.3%; validation cohort 2: AUC 0.81, 95% CI 0.73-0.88, sensitivity 69.1%, specificity 83.3%). Calibration plots for the nomogram showed excellent agreement between SAE probabilities of the observed and predicted values. Decision curve analysis indicated that the nomogram conferred a high net clinical benefit. CONCLUSIONS: The novel nomogram and online calculator showed performance in predicting the morbidity of SAE in patients with sepsis admitted to the PICU, thereby potentially assisting clinicians in the early detection and intervention of SAE.

DYRK1A is a multifunctional host factor that regulates coronavirus replication in a kinase-independent manner.

Coronaviruses (CoVs) pose a major threat to human and animal health worldwide, which complete viral replication by hijacking host factors. Identifying host factors essential for the viral life cycle can deepen our understanding of the mechanisms of virus-host interactions. Based on our previous genome-wide CRISPR screen of α-CoV transmissible gastroenteritis virus (TGEV), we identified the host factor dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), but not DYRK1B, as a critical factor in TGEV replication. Rescue assays and kinase inhibitor experiments revealed that the effect of DYRK1A on viral replication is independent of its kinase activity. Nuclear localization signal modification experiments showed that nuclear DYRK1A facilitated virus replication. Furthermore, DYRK1A knockout significantly downregulated the expression of the TGEV receptor aminopeptidase N (ANPEP) and inhibited viral entry. Notably, we also demonstrated that DYRK1A is essential for the early stage of TGEV replication. Transmission electron microscopy results indicated that DYRK1A contributes to the formation of double-membrane vesicles in a kinase-independent manner. Finally, we validated that DYRK1A is also a proviral factor for mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. In conclusion, our work demonstrated that DYRK1A is an essential host factor for the replication of multiple viruses, providing new insights into the mechanism of virus-host interactions and facilitating the development of new broad-spectrum antiviral drugs.IMPORTANCECoronaviruses, like other positive-sense RNA viruses, can remodel the host membrane to form double-membrane vesicles (DMVs) as their replication organelles. Currently, host factors involved in DMV formation are not well defined. In this study, we used transmissible gastroenteritis virus (TGEV) as a virus model to investigate the regulatory mechanism of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) on coronavirus. Results showed that DYRK1A significantly inhibited TGEV replication in a kinase-independent manner. DYRK1A knockout (KO) can regulate the expression of receptor aminopeptidase N (ANPEP) and endocytic-related genes to inhibit virus entry. More importantly, our results revealed that DYRK1A KO notably inhibited the formation of DMV to regulate the virus replication. Further data proved that DYRK1A is also essential in the replication of mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. Taken together, our findings demonstrated that DYRK1A is a conserved factor for positive-sense RNA viruses and provided new insights into its transcriptional regulation activity, revealing its potential as a candidate target for therapeutic design.

Platelet membrane-derived biomimetic microbubbles with enhanced targeting ability for the early detection of myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a widely recognized cardiovascular disease that significantly impacts the prognosis of patients undergoing myocardial infarction recanalization. This condition can be fatal and involves complex pathophysiological mechanisms. Early diagnosis of MIRI is crucial to minimize myocardial damage and reducing mortality. Based on the inherent relationship between platelets and MIRI, we developed biomimetic microbubbles coated with platelet membrane (MB-pla) for early identification of MIRI. The MB-pla were prepared through a recombination process involving platelet membrane obtained from rat whole blood and phospholipids, blended in appropriate proportions. By coating the microbubbles with platelet membrane, MB-pla acquired various adhesion molecules, thereby gaining the capability to selectively adhere to damaged endothelial cells in the context of MIRI. In vitro experiments demonstrated that MB-pla exhibited remarkable targeting characteristics, particularly toward type IV collagen and human umbilical vein endothelial cells that had been injured through hypoxia/reoxygenation procedures. In a rat model of MIRI, the signal intensity produced by MB-pla was notably higher than that of control microbubbles. These findings were consistent with results obtained from fluorescence imaging of isolated hearts and immunofluorescence staining of tissue sections. In conclusion, MB-pla has great potential as a non-invasive early detection method for MIRI. Furthermore, this approach can potentially find application in other conditions involving endothelial injury in the future.

Left atrial strain brings new insights for evaluating early diastolic dysfunction in patients with well-functioning bicuspid aortic valve.

BACKGROUND: Left atrial reservoir strain (LARS) is an early sensor of left ventricular (LV) diastolic dysfunction. Still, the clinical implications of LARS in patients with well-functioning bicuspid aortic valve (BAV) remain unknown. MATERIALS: The study recruited 103 patients with well-functioning BAV and 50 controls with tricuspid aortic valves. LARS, LV global longitudinal strain (LVGLS) and aortic elasticity indices (aortic strain, aortic distensibility and stiffness index) were acquired. This study aimed to analyze the changes of LARS and further explore the influential factors of LARS in patients with well-functioning BAV. RESULTS: Patients with BAV had lower LARS (34.17 ± 4.85 vs. 44.72 ± 6.06 %, P < .001) and LVGLS (20.53 ± 1.28 vs. 22.30 ± .62 %, P < .001), and abnormal aortic elasticity indices (aortic strain:7.14 ± 1.57 vs. 10.99 ± 1.03 %, aortic distensibility: 5.82 ± 1.50 vs. 8.98 ± 2.42 (10-6 cm2 dyne-1 ), and stiffness index: 6.30 ± 2.30 vs. 3.92 ± .98, all P < .05) compared with controls. LARS was associated with LVGLS (r = .799), interventricular septum index (r = -.232), lateral e' (r = .290), septal e' (r = .308), E/e' ratio (r = -.392), aortic strain (r = .829), aortic distensibility (r = .361), and stiffness index (r = -.724) (all P < .05). LVGLS, aortic strain and E/e' ratio were independent influencers of LARS in the multifactorial analysis model (all P < .05). CONCLUSION: In patients with well-functioning BAV, decreased LARS may provide evidence of subclinical LV diastolic function impairment. LARS may be helpful for clinical risk stratification in such a population.

Advance Progress in Assembly Mechanisms of Carrier-Free Nanodrugs for Cancer Treatment.

Nanocarriers have been widely studied and applied in the field of cancer treatment. However, conventional nanocarriers still suffer from complicated preparation processes, low drug loading, and potential toxicity of carriers themselves. To tackle the hindrance, carrier-free nanodrugs with biological activity have received increasing attention in cancer therapy. Extensive efforts have been made to exploit new self-assembly methods and mechanisms to expand the scope of carrier-free nanodrugs with enhanced therapeutic performance. In this review, we summarize the advanced progress and applications of carrier-free nanodrugs based on different types of assembly mechanisms and strategies, which involved noncovalent interactions, a combination of covalent bonds and noncovalent interactions, and metal ions-coordinated self-assembly. These carrier-free nanodrugs are introduced in detail according to their assembly and antitumor applications. Finally, the prospects and existing challenges of carrier-free nanodrugs in future development and clinical application are discussed. We hope that this comprehensive review will provide new insights into the rational design of more effective carrier-free nanodrug systems and advancing clinical cancer and other diseases (e.g., bacterial infections) infection treatment.

Short- and long-term outcomes of single-port versus multiport laparoscopic radical gastrectomy for gastric cancer: a meta-analysis of propensity score-matched studies and randomized controlled trials.

BACKGROUND: At present, there is no convincing evidence-based medical basis for the efficacy of single-port laparoscopic gastrectomy. To make a high-quality comparison of the short- and long-term outcomes of single-port laparoscopic gastrectomy versus multiport laparoscopic gastrectomy, we performed this meta-analysis, which only included propensity score-matched studies and randomized controlled trials comparing single-port laparoscopic gastrectomy with multiport laparoscopic gastrectomy for patients with gastric cancer. METHODS: Data were retrieved from the electronic databases PubMed, EMBASE, Medline, Cochrane Library, CNKI, Wanfang and VIP up to January 2023, and the data included the outcomes of treatment after single-port laparoscopic gastrectomy and multiport laparoscopic gastrectomy. The primary outcomes were early complications, survival rate after surgery at 1 year, and survival rate after surgery at 5 years. The secondary outcomes were number of pain medications, mean operation time, estimated blood loss, hospital mortality, time to first soft fluid diet, time to first flatus, hospital stay after surgery, and retrieved number of lymph nodes. The Jadad score and Newcastle‒Ottawa scale were used to assess the quality of the included studies. RESULTS: After screening, 9 studies were finally included, including 988 patients. The meta-analysis results showed that estimated blood loss (MD=-29.35, 95% CI: -42.95-15.75, P < 0.0001), hospital stay (MD=-0.99, 95% CI:-1.82~-0.17, P = 0.02), and number of pain medications(MD=-0.65, 95% CI:-1.07~-0.23, P = 0.002) in the single-port laparoscopic gastrectomy group were better than those in the multiport laparoscopic gastrectomy group. There is no significant difference between the single-port laparoscopic gastrectomy group and the multiport laparoscopic gastrectomy group in mean operation time(MD = 5.23,95% CI:-16.58~27.04,P = 0.64), time to first soft fluid diet(MD=-0.06,95% CI: -0.30~0.18,P = 0.63), time to first flatus(MD=-0.18,95% CI:-0.43~0.07,P = 0.16), early complication(OR = 0.73,95% CI:0.50~1.09,P = 0.12), hospital mortality(OR = 1.00,95% CI:0.09~11.16,P = 1.00), retrieved number of lymph nodes(MD=-1.15, 95% CI:-2.71~0.40, P = 0.15), survival rate after surgery 1 year(OR = 2.14,95% CI:0.50~9.07,P = 0.30), and survival rate after surgery 5 year(93.7 vs. 87.6%; p = 0.689). CONCLUSION: This meta-analysis showed that single-port laparoscopic gastrectomy is both safe and feasible for laparoscopic radical gastrectomy for gastric cancer, with similar operation times and better short-term outcomes than multiport laparoscopic gastrectomy in terms of hospital stay, postoperative pain, and estimated blood loss. There was no significant difference in long-term outcomes between single-port laparoscopic gastrectomy and multiport laparoscopic gastrectomy.

Ursolic acid reduces oxidative stress injury to ameliorate experimental autoimmune myocarditis by activating Nrf2/HO-1 signaling pathway.

Background: Oxidative stress is crucial in experimental autoimmune myocarditis (EAM)-induced inflammatory myocardial injury. Ursolic acid (UA) is an antioxidant-enriched traditional Chinese medicine formula. The present study aimed to investigate whether UA could alleviate inflammatory cardiac injury and determine the underlying mechanisms. Methods: Six-week-old male BALB/c mice were randomly assigned to one of the three groups: Sham, EAM group, or UA intervention group (UA group) by gavage for 2 weeks. An EAM model was developed by subcutaneous injection of α-myosin heavy chain derived polypeptide (α-MyHC peptide) into lymph nodes on days 0 and 7. Echocardiography was used to assess cardiac function on day 21. The inflammation level in the myocardial tissue of each group was compared using hematoxylin and eosin staining (HE) of heart sections and Interleukin-6 (IL-6) immunohistochemical staining. Masson staining revealed the degree of cardiac fibrosis. Furthermore, Dihydroethidium staining, Western blot, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to determine the mechanism of cardioprotective effects of UA on EAM-induced cardiac injury, and the level of IL-6, Nrf2, and HO-1. Results: In EAM mice, UA intervention significantly reduced the degree of inflammatory infiltration and myocardial fibrosis while improving cardiac function. Mechanistically, UA reduced myocardial injury by inhibiting oxidative stress (as demonstrated by a decrease of superoxide and normalization of pro- and antioxidant enzyme levels). Interestingly, UA intervention upregulated the expression of antioxidant factors such as Nrf2 and HO-1. In vitro experiments, specific Nrf2 inhibitors reversed the antioxidant and antiapoptotic effects of ursolic acid, which further suggested that the amelioration of EAM by UA was in a Nrf2/HO-1 pathway-dependent manner. Conclusion: These findings indicate that UA is a cardioprotective traditional Chinese medicine formula that reduces EAM-induced cardiac injury by up-regulating Nrf2/HO-1 expression and suppressing oxidative stress, making it a promising therapeutic strategy for the treatment of EAM.

mLST8 is essential for coronavirus replication and regulates its replication through the mTORC1 pathway.

Coronaviruses (CoVs), which pose a serious threat to human and animal health worldwide, need to hijack host factors to complete their replicative cycles. However, the current study of host factors involved in CoV replication remains unknown. Here, we identified a novel host factor, mammalian lethal with sec-13 protein 8 (mLST8), which is a common subunit of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and is critical for CoV replication. Inhibitor and knockout (KO) experiments revealed that mTORC1, but not mTORC2, is essential for transmissible gastroenteritis virus replication. Furthermore, mLST8 KO reduced the phosphorylation of unc-51-like kinase 1 (ULK1), a factor downstream of the mTORC1 signaling pathway, and mechanistic studies revealed that decreased phosphorylation of the mTORC1 downstream factor ULK1 promoted the activation of autophagy, which is responsible for antiviral replication in mLST8 KO cells. Then, transmission electron microscopy indicated that both mLST8 KO and autophagy activator inhibited the formation of double-membrane vesicles in early viral replication. Finally, mLST8 KO and autophagy activator treatment could also inhibit the replication of other CoVs, indicating a conserved relationship between autophagy activation and CoV replication. In summary, our work reveals that mLST8 is a novel host regulator of CoV replication, which provides new insights into the mechanism of CoV replication and can facilitate the development of broad-spectrum antiviral drugs. IMPORTANCE CoVs are highly variable, and existing CoV vaccines are still limited in their ability to address mutations in CoVs. Therefore, the need to improve our understanding of the interaction of CoVs with the host during viral replication and to find targets for drugs against CoVs is urgent. Here, we found that a novel host factor, mLST8, is critical for CoV infection. Further studies showed that mLST8 KO inhibited the mTORC1 signaling pathway, and we found that autophagy activation downstream of mTORC1 was the main cause of antiviral replication in mLST8 KO cells. Autophagy activation impaired the formation of DMVs and inhibited early viral replication. These findings deepen our understanding of the CoV replication process and provide insights into potential therapeutic applications.

Decreased ventricular systolic function in chemotherapy-naive patients with acute myeloid leukemia: a three-dimensional speckle-tracking echocardiography study.

Background: The relationship between acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) and cardiac function is not well established. This study aimed to evaluate whether AML patients exist early myocardial damages prior to chemotherapy and to investigate its association with cardiovascular biomarkers. Methods: Conventional echocardiography and three-dimensional speckle-tracking strain analysis were performed prospectively in 72 acute leukemia (AL) patients before any chemotherapy therapy (of whom 44 were AML patients, 28 ALL patients). The results were compared with those from 58 control group matched for age and gender. Results: There were no significant differences in conventional biventricular systolic function parameters between AL patients and controls. The left ventricular global longitudinal strain (LVGLS) and right ventricular free wall longitudinal strain (RVFWLS) were significantly lower in AL patients (-23.0 ± 1.4% vs. -24.1 ± 1.3% and -27.9 ± 7.1% vs. -33.0 ± 4.6%, respectively, P < 0.001 for all). Compared with ALL patients, AML patients had lower LVGLS and RVFWLS (-22.7 ± 1.3% vs. -23.5 ± 1.6% and -26.2 ± 7.6% vs. -30.4 ± 5.5%, respectively, P < 0.05 for all). LVGLS was lower in ALL patients compared with controls (-23.5 ± 1.6% vs. -24.7 ± 1.4%, P < 0.05), however, there was no difference in right ventricular systolic function parameters between the two groups. LVGLS in AL patients was independently correlated with left ventricular ejection fraction (LVEF) and the absolute number of circulating lymphocytes. Conclusions: Our findings suggest that baseline myocardial systolic function is lower in AL patients than controls. AML patients had lower baseline LVGLS and RVFWLS than controls and ALL patients. The decreased LVGLS is correlated with LVEF and the absolute number of circulating lymphocytes.

Chelate-Capped Nano-AgZn3 Dual Interphase Remodeling the Local Environment for Reversible Dendrite-Free Zinc Anode.

Rechargeable aqueous zinc-ion batteries (AZIBs) are among the most promising candidates for next-generation energy-storage devices. However, the large voltage polarisation and infamous dendrite growth hinder the practical application of AZIBs owing to their complex interfacial electrochemical environment. In this study, a hydrophobic zinc chelate-capped nano-silver (HZC-Ag) dual interphase is fabricated on the zinc anode surface using an emulsion-replacement strategy. The multifunctional HZC-Ag layer remodels the local electrochemical environment by facilitating the pre-enrichment and de-solvation of zinc ions and inducing homogeneous zinc nucleation, thus resulting in reversible dendrite-free zinc anodes. The zinc deposition mechanism on the HZC-Ag interphase is elucidated by density functional theory (DFT) calculations, dual-field simulations, and in situ synchrotron X-ray radiation imaging. The HZC-Ag@Zn anode exhibited superior dendrite-free zinc stripping/plating performance and an excellent lifespan of >2000 h with ultra-low polarisation of ≈17 mV at 0.5 mA cm-2 . Full cells coupled with a MnO2 cathode showed significant self-discharge inhibition, excellent rate performance, and improved cycling stability for >1000 cycles. Therefore, this multifunctional dual interphase may contribute to the design and development of dendrite-free anodes for high-performance aqueous metal-based batteries.

Noninvasive ultrasound stimulation to treat myocarditis through splenic neuro-immune regulation.

BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) has been widely studied to modulate the immune response. Current stimulating strategies are invasive or imprecise. Noninvasive low-intensity pulsed ultrasound (LIPUS) has become increasingly appreciated for targeted neuronal modulation. However, its mechanisms and physiological role on myocarditis remain poorly defined. METHODS: The mouse model of experimental autoimmune myocarditis was established. Low-intensity pulsed ultrasound was targeted at the spleen to stimulate the spleen nerve. Under different ultrasound parameters, histological tests and molecular biology were performed to observe inflammatory lesions and changes in immune cell subsets in the spleen and heart. In addition, we evaluated the dependence of the spleen nerve and cholinergic anti-inflammatory pathway of low-intensity pulsed ultrasound in treating autoimmune myocarditis in mice through different control groups. RESULTS: The echocardiography and flow cytometry of splenic or heart infiltrating immune cells revealed that splenic ultrasound could alleviate the immune response, regulate the proportion and function of CD4+ Treg and macrophages by activating cholinergic anti-inflammatory pathway, and finally reduce heart inflammatory injury and improve cardiac remodeling, which is as effective as an acetylcholine receptor agonists GTS-21. Transcriptome sequencing showed significant differential expressed genes due to ultrasound modulation. CONCLUSIONS: It is worth noting that the ultrasound therapeutic efficacy depends greatly on acoustic pressure and exposure duration, and the effective targeting organ was the spleen but not the heart. This study provides novel insight into the therapeutic potentials of LIPUS, which are essential for its future application.

Nrf2 silencing amplifies DNA photooxidative damage to activate the STING pathway for synergistic tumor immunotherapy.

Photodynamic therapy (PDT)-mediated antitumor immune response depends on oxidative stress intensity and subsequent immunogenic cell death (ICD) in tumor cells, yet the inherent antioxidant system restricts reactive oxygen species (ROS)-associated oxidative damage, which is highly correlated with the upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream products, such as glutathione (GSH). Herein, to overcome this dilemma, we designed a versatile nanoadjuvant (RI@Z-P) to enhance the sensitivity of tumor cells to oxidative stress via Nrf2-specific small interfering RNA (siNrf2). The constructed RI@Z-P could significantly amplify photooxidative stress and achieve robust DNA oxidative damage, activating the stimulator of interferon genes (STING)-dependent immune-sensing to produce interferon-ß (IFN-ß). Additionally, RI@Z-P together with laser irradiation reinforced tumor immunogenicity by exposing or releasing damage-associated molecular patterns (DAMPs), showing the prominent adjuvant effect for promoting dendritic cell (DC) maturation and T-lymphocyte activation and even alleviating the immunosuppressive microenvironment to some extent.

Humic acid chelated selenium is suitable for wheat biofortification.

BACKGROUND: Selenium rich bread is a good carrier of selenium, but the inorganic selenium used in the actual production process is toxic. It is necessary to develop a new green bread production technology. The extraction and utilization of humic acid chelated selenium from selenium-rich soil is beneficial for reducing resource waste and pollution without destroying the soil ecosystem in selenium-deficient areas. Sodium selenite and nanoselenium were selected as controls because they are commonly used as selenium agronomic enhancers in production. RESULTS: Humic acid chelated selenium can be absorbed and accumulated by wheat leaves, and humic acid chelated selenium had no significant effect on wheat yield, which was also shown in the treatments with nanoselenium and sodium selenite. Excessive accumulation of selenium in wheat grains can lead to a deterioration of processing quality. Among them, the use of excessive nanoselenium at the filling stage inhibited the accumulation of wheat grain protein, whereas humic acid chelated selenium is beneficial to grain protein accumulation and has the least negative effect on the processing quality. The accumulation of excessive selenium in wheat seeds had a negative effect on seed germination and growth; specifically, the seed vigor of wheat treated with humic acid chelated selenium was higher than that of untreated wheat. CONCLUSION: Humic acid chelated selenium is particularly suitable for the whole process of Se-enriched bread wheat production. The seed vigour of wheat treated with humic acid chelated selenium, which supplied a moderate amount of selenium, was higher than that of untreated wheat. Conversely, the accumulation of excessive selenium in wheat seeds reduced germination and seedling growth. © 2023 Society of Chemical Industry.

Temporal effect of the spin-to-orbit conversion in tightly focused femtosecond optical fields.

Spin and orbital angular momenta are two of the most fundamental physical quantities that describe the complex dynamic behaviors of optical fields. A strong coupling between these two quantities leads to many intriguing spatial topological phenomena, where one remarkable example is the generation of a helicity-dependent optical vortex that converts spin to orbital degrees of freedom. The spin-to-orbit conversion occurs inherently in lots of optical processes and has attracted increasing attention due to its crucial applications in spin-orbit photonics. However, current researches in this area are mainly focused on the monochromatic optical fields whose temporal properties are naturally neglected. In this work, we demonstrate an intriguing temporal evolution of the spin-to-orbit conversion induced by tightly-focused femtosecond optical fields. The results indicate that the conversion in such a polychromatic focused field obviously depends on time. This temporal effect originates from the superposition of local fields at the focus with different frequencies and is sensitive to the settings of pulse width and central wavelength. This work can provide fundamental insights into the spin-orbit dynamics within ultrafast wave packets, and possesses the potential for applications in spin-controlled manipulations of light.

New trends in non-pharmacological approaches for cardiovascular disease: Therapeutic ultrasound.

Significant advances in application of therapeutic ultrasound have been reported in the past decades. Therapeutic ultrasound is an emerging non-invasive stimulation technique. This approach has shown high potential for treatment of various disease including cardiovascular disease. In this review, application principle and significance of the basic parameters of therapeutic ultrasound are summarized. The effects of therapeutic ultrasound in myocardial ischemia, heart failure, myocarditis, arrhythmias, and hypertension are explored, with key focus on the underlying mechanism. Further, the limitations and challenges of ultrasound therapy on clinical translation are evaluated to promote application of the novel strategy in cardiovascular diseases.