Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age.

BACKGROUND: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 µg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS: In part 1 of the trial, 751 children received 50-µg or 100-µg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-µg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 µg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-µg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-µg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS: Two 50-µg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Evaluation of mRNA-1273 Vaccine in Children 6 Months to 5 Years of Age.

BACKGROUND: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-µg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo. RESULTS: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-µg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-µg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-µg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant. CONCLUSIONS: Two 25-µg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Safety and Immunogenicity of an mRNA-1273 Booster in Children.

BACKGROUND: A 2-dose mRNA-1273 primary series in children aged 6 months-5 years (25-µg) and 6-11 years (50-µg) had an acceptable safety profile and was immunogenic in the phase 2/3 KidCOVE study. We present data from KidCOVE participants who received an mRNA-1273 booster dose. METHODS: An mRNA-1273 booster dose (10-µg for children aged 6 months-5 years; 25-µg for children aged 6-11 years; age groups based on participant age at enrollment) was administered ≥6 months after primary series completion. The primary safety objective was the safety and reactogenicity of an mRNA-1273 booster dose. The primary immunogenicity objective was to infer efficacy of an mRNA-1273 booster dose by establishing noninferiority of neutralizing antibody (nAb) responses after a booster in children compared with nAb responses observed after the mRNA-1273 primary series in young adults (18-25 years) from the pivotal efficacy study. Data were collected from March 2022 to June 2023. RESULTS: Overall, 153 (6 months-5 years) and 2519 (6-11 years) participants received an mRNA-1273 booster dose (median age at receipt of booster: 2 and 10 years, respectively). The booster dose safety profile was generally consistent with that of the primary series in children; no new safety concerns were identified. An mRNA-1273 booster dose elicited robust nAb responses against ancestral SARS-CoV-2 among children and met prespecified noninferiority success criteria when compared with responses observed after the primary series in young adults. CONCLUSIONS: Safety and immunogenicity data support administration of a mRNA-1273 booster dose in children aged 6 months to 11 years. CLINICAL TRIALS REGISTRATION: NCT04796896.

Pt-Cluster-Embedded Metal-Organic Frameworks-Derived Fe@C as Dual-Enzyme Mimics for NADH Detection in Serum.

Dihydro-nicotinamide adenine dinucleotide (NADH) detection is crucial since it is a vital coenzyme in organism metabolism. Compared to the traditional method based on natural NADH oxidase (NOX), nanozymes with multienzyme-like activity can catalyze multistage reactions in a singular setup, simplifying detection processes and enhancing sensitivity. In this study, an innovative NADH detection method was developed using iron-doped carbon (Fe@C) nanozyme synthesized from metal-organic frameworks with in situ reduced Pt clusters. This nanozyme composite (Pt/Fe@C) demonstrated dual NOX and peroxidase-like characteristics, significantly enhancing the catalytic efficiency and enabling NADH conversion to NAD+ and H2O2 with subsequent detection. The collaborative research involving both experimental and theoretical simulations has uncovered the catalytic process and the cooperative effect of Fe and Pt atoms, leading to enhanced oxygen adsorption and activation, as well as a decrease in the energy barrier of the key step in the H2O2 decomposition process. These findings indicate that the catalytic performance of Pt/Fe@C in NOX-like and POD-like reactions can be significantly improved. The colorimetric sensor detects NADH with a limit of detection as low as 0.4 nM, signifying a breakthrough in enzyme-mimicking nanozyme technology for precise NADH measurement.

Impact of preoperative transcatheter arterial chemoembolization (TACE) on postoperative long-term survival in patients with nonsmall hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND: The purpose of this propensity score matching (PSM) analysis was to compare the effects of preoperative transcatheter arterial chemoembolization (TACE) and non-TACE on the long-term survival of patients who undergo radical hepatectomy. METHODS: PSM analysis was performed for 387 patients with hepatocellular carcinoma (HCC) (single > 3 cm or multiple) who underwent radical resection of HCC at our centre from January 2011 to June 2018. The patients were allocated to a preoperative TACE group (n = 77) and a non-TACE group (n = 310). The main outcome measures were progression-free survival (PFS) and overall survival (OS) since the treatment date. RESULTS: After PSM, 67 patients were included in each of the TACE and non-TACE groups. The median PFS times in the preoperative TACE and non-TACE groups were 24.0 and 11.3 months, respectively (p = 0.0117). The median OS times in the preoperative TACE and non-TACE groups were 41.5 and 29.0 months, respectively (p = 0.0114). Multivariate Cox proportional hazard regression analysis revealed that preoperative TACE (hazard ratio, 1.733; 95% CI, 1.168-2.570) and tumour thrombosis (hazard ratio, 0.323; 95% CI, 0.141-0.742) were independent risk factors significantly associated with OS. CONCLUSIONS: Preoperative TACE is related to improving PFS and OS after resection of HCC. Preoperative TACE and tumour thrombus volume were also found to be independent risk factors associated with OS.

[Identification of cardioprotective substances in Panax ginseng/P. notoginseng based on mitochondrial morphological characteristics and UPLC-Triple-TOF-MS].

Panax ginseng is reputed to be capable of replenishing healthy Qi and bolstering physical strength, and P. notoginseng can resolve blood stasis and alleviate pain. P. ginseng and P. notoginseng are frequently employed to treat ischemic heart diseases caused by blockages in the heart vessels. Mitochondrial dysfunction often coexists with abnormal mitochondrial morphology, and mitochondrial plasticity and dynamics play key roles in cardiovascular diseases. In this study, primary neonatal rat cardiomyocytes were exposed to 4 hours of hypoxia(H) followed by 2 hours of reoxygenation(R). MitoTracker Deep Red and Hoechst 33342 were used to label mitochondria and nuclei, respectively. Fluorescence images were then acquired using ImageXpress Micro Confocal. Automated image processing and parameter extraction/calculation were carried out using ImagePro Plus. Subsequently, representative parameters were selected as indicators to assess alterations in mitochondrial morphology and function. The active compounds of P. ginseng and P. notoginseng were screened out and identified based on the UPLC-Triple-TOF-MS results and mitochondrial morphometric parameters. The findings demonstrated that RS-2, RS-4, SQ-1, and SQ-4 significantly increased the values of three key morphometric parameters, including mitochondrial length, branching, and area, which might contribute to rescuing morphological features of myocardial cells damaged by H/R injury. Among the active components of the two medicinal herbs, 20(R)-ginsenoside Rg_3, ginsenoside Re, and gypenoside ⅩⅦ exhibited the strongest protective effects on mitochondria in cardiomyocytes. Specifically, 20(R)-ginsenoside Rg_3 might upregulate expression of optic atrophy 1(OPA1) and mitofusin 2(MFN2), and ginsenoside Re and gypenoside ⅩⅦ might selectively upregulate OPA1 expression. Collectively, they promoted mitochondrial membrane fusion and mitigated mitochondrial damage, thereby exerting protective effects on cardiomyocytes. This study provides experimental support for the discovery of novel therapeutic agents for myocardial ischemia-reperfusion injury from P. ginseng and P. notoginseng and offers a novel approach for large-scale screening of bioactive compounds with cardioprotective effects from traditional Chinese medicines.

MIL-101(CuFe) Nanozymes with Excellent Peroxidase-like Activity for Simple, Accurate, and Visual Naked-Eye Detection of SARS-CoV-2.

The COVID-19 pandemic has spread to every corner of the world and seriously affected our health and daily activities in the past three years; thereby, it is still urgent to develop various simple, quick, and accurate methods for early detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Nanozymes, a kind of nanomaterial with intrinsic enzyme-mimicking activity, have emerged as a suitable alternative for both therapy and diagnosis of SARS-CoV-2. Here, ultrasensitive and ultrafast MIL-101(CuFe)-CD147 biosensors are established for the detection of SARS-CoV-2 by a simple colorimetric method. A MIL-101(CuFe) metal-organic framework has excellent peroxidase-like activity due to the synergistic effect of Fe and Cu atoms. In addition, the MIL-101(CuFe)-CD147 biosensor shows great potential to detect the various variants of SARS-CoV-2 due to the universal receptor of CD147. The enzyme-based biosensor for the detection of SARS-CoV-2 achieves a very low limit of detection (about 3 PFU/mL) within 30 min. Therefore, the present method provides a new generation of an alternative approach for highly sensitive and visual diagnosis of COVID-19.

Covalent Immobilization of Natural Biomolecules on Chitin Nanocrystals.

As a highly crystalline and renewable natural polymer nanomaterial, chitin nanocrystals (ChNCs) have attracted intense interest in the biomedical field. The structure of a ChNC is composed of an acetylglucosamine unit containing two hydroxyl groups and an acetyl group. The acetyl group can be converted to the active amino group through deacetylation, which is under the condition of maintaining the rod-like morphology and high crystalline property and is beneficial for the following modification and potential application. We investigated the relationship between different treatments and varied crystallinities of the modified ChNC, which obtained surface amino groups and aldehyde groups and retained high crystallinity. The natural biomolecules were covalently immobilized on the surface of the ChNC. The etherification was performed based on the hydroxyl groups. Based on the amino groups and the aldehyde groups, the carboxyamine and Knoevenagel condensation reactions were realized on ChNCs. Finally, natural biomolecule-modified ChNCs showed no or low cytotoxicity, antibacterial properties, and high antioxidant properties, which extended their potential biomedical applications.

[Application of transport ventilator in the inter-hospital transport of critically ill children]. / è½¬è¿å‘¼å¸æœºåœ¨å±é‡æ‚£å„¿é™¢é™ è½¬è¿ä¸­çš„åº”ç”¨ç ”ç©¶.

OBJECTIVES: To study the application value of transport ventilator in the inter-hospital transport of critically ill children. METHODS: The critically ill children in Hunan Children's Hospital who were transported with or without a transport ventilator were included as the observation group (from January 2019 to January 2020; n=122) and the control group (from January 2018 to January 2019; n=120), respectively. The two groups were compared in terms of general data, the changes in heart rate, respiratory rate, and blood oxygen saturation during transport, the incidence rates of adverse events, and outcomes. RESULTS: There were no significant differences between the two groups in sex, age, oxygenation index, pediatric critical illness score, course of disease, primary disease, heart rate, respiratory rate, and transcutaneous oxygen saturation before transport (P>0.05). During transport, there were no significant differences between the two groups in the changes in heart rate, respiratory rate, and transcutaneous oxygen saturation (P>0.05). The incidence rates of tracheal catheter detachment, indwelling needle detachment, and sudden cardiac arrest in the observation group were lower than those in the control group during transport, but the difference was not statistically significant (P>0.05). Compared with the control group, the observation group had significantly shorter duration of mechanical ventilation and length of stay in the pediatric intensive care unit and significantly higher transport success rate and cure/improvement rate (P<0.05). CONCLUSIONS: The application of transport ventilator in the inter-hospital transport can improve the success rate of inter-hospital transport and the prognosis in critically ill children, and therefore, it holds promise for clinical application in the inter-hospital transport of critically ill children.

HSP90/IKK-rich small extracellular vesicles activate pro-angiogenic melanoma-associated fibroblasts via the NF-κB/CXCL1 axis.

Hypoxia is a main feature of most solid tumors, but how melanoma cells under hypoxic conditions exploit tumor microenvironment (TME) to facilitate tumor progression remains poorly understood. In this study, we found that hypoxic melanoma-derived small extracellular vesicles (sEVs) could improve the proangiogenic capability of cancer-associated fibroblasts (CAFs). This improvement was due to the activation of the IKK/IκB/NF-κB signaling pathway and upregulation of CXCL1 expression and secretion in CAFs. By proteomic analysis, we verified that hypoxia could promote enrichment of chaperone HSP90 and client protein phosphorylated IKKα/ß (p-IKKα/ß) in melanoma-derived sEVs. Delivery of the HSP90/p-IKKα/ß complex by sEVs could activate the IKK/IκB/NF-κB/CXCL1 axis in CAFs and promote angiogenesis in vitro and in vivo. Taken together, these findings deepen the understanding of hypoxic response in melanoma progression and provide potential targets for melanoma treatment.

Gold Nanorods/Metal-Organic Framework Hybrids: Photo-Enhanced Peroxidase-Like Activity and SERS Performance for Organic Dyestuff Degradation and Detection.

Metal-organic frameworks (MOFs) are widely used to mimic enzymes for catalyzing chemical reactions; however, low enzyme activity limit their large-scale application. In this work, gold nanorods/metal-organic frameworks (Au NRs/Fe-MOF) hybrids were successfully synthesized for photo-enhanced peroxidase-like catalysis and surface-enhanced Raman spectroscopy (SERS). The enzyme-like activity of Au NRs/Fe-MOF hybrids was significantly enhanced under localized surface plasmon resonance (LSPR), because the hot electrons produced on Au NRs surface were transferred into Fe-MOF, activating the Fenton reaction by Fe3+/Fe2+ conversion and preventing the recombination of hot electrons and holes. This photo-enhanced enzyme-like catalytic performance was investigated by X-ray photoelectron spectrometry (XPS), electrochemical analysis, activation energy measurement, and in situ Raman spectroscopy. Afterward, Methylene Blue (MB) was chosen to demonstrate the photo-enhanced peroxidase-like performance of Au NRs/Fe-MOFs. The Au NRs/Fe-MOF caused chemical and electromagnetic enhancement of Raman signals and exhibited a great potential for the detection of toxic chemicals and biological molecules. The detection limit of MB concentration is 9.3 × 10-12 M. In addition, the Au NRs/Fe-MOF hybrids also showed excellent stability and reproducibility for photo-enhanced peroxidase-like catalysis. These results show that nanohybrids have great potential in many fields, such as sensing, cancer therapy, and energy harvesting.

Nanotechnology-based chimeric antigen receptor T-cell therapy in treating solid tumor.

Chimeric Antigen Receptor (CAR) T cells have changed the therapeutic landscape of hematological malignancies with overwhelming success. The clinical success of CAR T-cell therapy in hematologic malignancies has fueled interest in exploring the technology in solid tumors. However, the treatment of solid tumors presents a unique set of challenges compared to hematological tumors. The biggest impediments to the success of CAR T cell treatment are the paucity of tumor-specific antigens that are produced selectively and uniformly and the immunosuppressive tumor microenvironment. To overcome these significant challenges, nanotechnology has been involved to improve the efficacy of CAR-T cells. In this review, we systematically introduced the components of different generations of CARs and summarized recent innovations in nano-based CAR-T cell therapy to conquer therapeutically resistant non-hematologic malignancies, including mRNA and hydrogel-based CAR T cells delivery, photothermal-remodeling, and tumor microenvironment-based CAR T cell therapy. These nanotechnologies remarkably facilitate in vivo generation of CAR T cells and hold promise as a therapeutic platform to treat solid tumors and even other diseases.

A Novel Joint Adversarial Domain Adaptation Method for Rotary Machine Fault Diagnosis under Different Working Conditions.

In real-world applications of detecting faults, many factors-such as changes in working conditions, equipment wear, and environmental causes-can cause a significant mismatch between the source domain on which classifiers are trained and the target domain to which those classifiers are applied. As such, existing deep network algorithms perform poorly under different working conditions. To solve this problem, we propose a novel fault diagnosis method named Joint Adversarial Domain Adaptation (JADA) for fault detection under different working conditions. Our approach simultaneously aligns marginal distribution and conditional distribution across the source and target through a unified adversarial learning process. JADA aims to construct domain-invariant and category-discriminative feature representation that is effective and robust for substantial distribution difference caused by working conditions. We also introduce a supervision signal, namely center loss, that penalizes the distances between the deep features and their corresponding class centers. This makes the learned features better equipped with more discriminative structures and effectively prevents mode collapse. Twenty-four transfer fault diagnosis tasks based on two experimental platforms were conducted to evaluate the effectiveness of the proposed methods. Extensive experiments verified that the JADA can significantly outperform several popular methods under different transfer diagnosis tasks.

[Mechanism of Guanxinning against cerebral ischemia-reperfusion injury in mice based on transcriptomic analysis].

Guanxinning, a modern Chinese medicine preparation composed of Salviae Miltiorrhizae Radix et Rhizoma and Chuanxiong Rhizoma, has the activities of activating blood circulation, resolving blood stasis, dredging vessels, and nourishing the heart. Clinical studies have demonstrated that Guanxinning has therapeutic effect on ischemic stroke, while the specific mechanism remains to be clarified. In this study, the potential mechanism of Guanxinning against cerebral ischemia-reperfusion injury in mice was explored and then verified in vitro. The mouse model of cerebral ischemia-reperfusion injury was established with middle cerebral artery embolization(MCAO) method. The pharmacological effects of Guanxinning on the model mice were investigated based on neurological function score, cerebral infarction area, pathological morphology, neuron injury, and apoptosis. The results showed that Guanxinning lowered neurological functional score, reduced cerebral infarction area, and ameliorated the histopathological morphology, neuronal damage, and apoptosis in the model mice. RNA samples were extracted from brain tissues and subjected to RNA sequencing(RNA-seq). The differentially expressed genes(DEGs) were screened with the thresholds of ■. GO function enrichment analysis and KEGG pathway enrichment analysis were performed for the 297 common DEGs, which indicated that Guanxinning may regulate the inflammatory response, oxidative stress response, energy metabolism, and apoptosis to treat cerebral ischemia-reperfusion injury in mice. Guanxinning exerted protective effect through inhibiting inflammation and reducing oxidative stress in hypoxia/reoxygenation injured SH-SY5 Y cells. Furthermore, Western blot indicated that Guanxinning down-regulated the protein levels of p-NF-κB p65 and p-p38 MAPK and up-regulated those of PPARγ and PGC-1α. The findings suggested that Guanxinning may inhibit inflammation and reduce oxidative stress by suppressing TNF signaling pathway and activating PPAR signaling pathway, thereby exerting the therapeutic effect on cerebral ischemia-reperfusion injury in mice. This study preliminarily reveals the mechanism of Guanxinning against cerebral ischemia-reperfusion injury and provides a basis for clinical application of Guanxinning.

[Theoretical innovation of component-based Chinese medicine and its exemplary practice: the study on creating Guanxinning Tablets].

Upholding the wisdom of traditional Chinese medicine that the therapeutic principle, method, formula and medicine are coherent with each other, we propose the technical methodology for intelligent creation of component-based Chinese medicine by integrating multidisciplinary knowledge such as artificial intelligence, pharmaceutical informatics, system pharmacology and phytochemistry. Taking the creation of Guanxinning Tablets as an example, we expound the technical principle for creating component-based Chinese medicine and briefly describe the design method for optimizing the entity of Chinese medicine efficacy by rational combination of active components. Our research sought to "clarify and explain" the mechanism of its clinical treatment action through multi-modal and multi-scale systematic pharmacology studies. This work emphatically demonstrates the pilot workshop and engineering validation platform based on the intelligent simulation of whole production process, and outlines the design principles of the intelligent production line for innovative Chinese medicine. The results of industrial research show that the ourself established method for evaluating the process quality controllability and intelligent production line can be applied to manufacturing Guanxining Tablets with high quality. Through the innovative research of multidisciplinary cross-border integration, the present work explored a new way for the creation of modern Chinese medicine.

[Effects of Angong Niuhuang Pills against heart failure based on cross-scale polypharmacological study].

Angong Niuhuang Pills(AGNHP) are effective in clearing heat, removing the toxin, and eliminating phlegm for resuscitation. Clinically, it is widely used to treat various diseases such as febrile convulsion due to heat attacking pericardium, but its therapeutic effects on heart failure(HF) have not been well recognized. In this study, the profiles of differential metabolites regulated by AGNHP were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). The underlying mechanism of AGNHP against HF was illustrated based on the integrated analysis of pharmacological data and metabolic molecular network. The HF model was induced by isoproterenol in mice. After oral administration of AGNHP for one week, cardiac functions in HF mice were evaluated by echocardiography, and serum samples of mice were collected for metabolomics analysis. Eight differential metabolites of AGNHP against HF were screened out through partial least square discriminant analysis(PLS-DA) and input into MetaboAnalyst for the analysis of metabolic pathways. Moreover, the critical metabolic pathways regulated by AGNHP were enriched according to the potential targets of major compounds in AGNHP. After AGNHP treatment, the recovered index of relative content of some metabolites underwent cross-scale fusion analysis with therapeutic efficacy data, followed by "compound-reaction-enzyme-gene" network analysis. It is inferred that the anti-HF effects of AGNHP may be attributed to the metabolism of arachidonic acid, amino acid, glycerophospholipid, and linoleic acid. The cross-scale polypharmacological analysis method developed in this study provides a new method to interpret scientific principles of AGNHP against HF with modern technologies.

Systematic analysis of immune-related genes based on a combination of multiple databases to build a diagnostic and a prognostic risk model for hepatocellular carcinoma.

The immune microenvironment plays a vital role in the progression of hepatocellular carcinoma (HCC). Thousands of immune-related genes (IRGs) have been identified, but their effects on HCC are not fully understood. In this study, we identified the differentially expressed IRGs and analyzed their functions in HCC in a systematic way. Furthermore, we constructed a diagnostic and a prognostic model using multiple statistical methods, and both models had good distinguishing performance, which we verified in several independent datasets. This diagnostic model was also adaptable to proteomic data. The combination of a prognostic risk model and classic clinical staging can effectively distinguish patients in high- and low-risk groups. Furthermore, we systematically explore the differences in the immune microenvironment between the high-risk group and the low-risk group to help clinical decision-making. In summary, we systematically analyzed immune-related genes in HCC, explored their functions, constructed a diagnostic and a prognostic model and investigated potential therapeutic schedules in high-risk patients. The model performance was verified in multiple databases. Our findings can provide directions for future research.

Nogo-B fosters HCC progression by enhancing Yap/Taz-mediated tumor-associated macrophages M2 polarization.

Tumor-associated macrophages (TAMs) and their M2-type extremely promote tumor angiogenesis, invasion and metastasis, including hepatocellular carcinoma (HCC). Nogo-B is expressed in most tissues and participates in macrophage polarization. However, whether Nogo-B is involved in the polarization and the effects of TAMs has been unclear. The expression of Nogo-B in TAMs of HCC patients is significantly increased, which correlated with the poor prognosis of the patients with HCC. Coincidentally, HCC conditioned medium (HCM) facilitated Nogo-B expression and the M2 phenotype of macrophages. Nogo-B knockdown Nogo-B significantly suppressed the M2-type polarization of macrophages and inhibited HCC cells proliferation both in vivo and in vitro. Furthermore, interference of Nogo-B facilitates macrophage-mediated apoptosis of tumor cells. Nogo-B meaningfully enhanced IL4-stimulated the alternative activation of macrophages as well as expression of the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz). An inhibitor of Yap, Verteporfin, could block Nogo-B-Yap/Taz-mediated macrophages M2 polarization. Nogo-B expression in macrophages facilitates tumor-associated macrophages M2 polarization and protumoral effects of TAMs in HCC. Targeting Nogo-B/Yap/Taz in macrophages could provide a new therapeutic strategy in HCC therapy.

Dendrimer-Au Nanoparticle Network Covered Alumina Membrane for Ion Rectification and Enhanced Bioanalysis.

Ion transport in an artificial asymmetric nanoporous membrane, which is similar to biological ion channels, can be used for biosensing. Here, a dendrimer-Au nanoparticle network (DAN) is in situ assembled on a nanoporous anodic aluminum oxide (AAO) surface, forming a DAN/AAO hybrid membrane. Benefiting from the high surface area and anion selectivity of DAN, the prepared DAN/AAO hybrid presents selective ion transport. Under a bias potential, a diode-like current-potential (I-V) response is observed. The obtained ionic current rectification (ICR) property can be tuned by the ion valence and pH value of the electrolyte. The rectified ionic current endows the as-prepared DAN/AAO hybrid with the ability of enhanced bioanalysis. Sensitive capture and detection of circulating tumor cells (CTCs) with a detection limit of 80 cells mL-1 as well as excellent reusability can be achieved.

Ultrasensitive and Label-Free Detection of Cell Surface Glycan Using Nanochannel-Ionchannel Hybrid Coupled with Electrochemical Detector.

In this work, asymmetric nanochannel-ionchannel of porous anodic alumina (PAA) coupled with electrochemical detector was used for sensitive and label-free detection of cell surface glycan. The amplified ionic current caused by array nanochannels as well as the ionic current rectification (ICR) caused by asymmetric geometry endows PAA with sensitive ionic current response. Functionalized with the special molecular probe, the constructed nanofluidic device can be used for selective recognition and detection of glycan in a real-time and label-free format. In addition, due to the subnanosize of ionchannels, the probe immobilization and glycan recognition is carried out on the outer surface of PAA, avoiding the blockage of PAA nanochannel by samples, which promises the reproducibility and accuracy of the present method toward bioanalysis. Results show that the glycan concentration ranging from 10 fM to 10 nM can be successfully detected with a detection limit of ∼10 aM, which is substantially lower than most previous works. The designed strategy provides a valuable platform for sensitive and label-free detection of cell surface glycan, which acts as a promising candidate in pathological research and cancer diagnosis.