Will AMPK be a potential therapeutic target for hepatocellular carcinoma?

Cancer is the disease that poses the greatest threat to human health today. Among them, hepatocellular carcinoma (HCC) is particularly prominent due to its high recurrence rate and extremely low five-year postoperative survival rate. In addition to surgical treatment, radiotherapy, chemotherapy, and immunotherapy are the main methods for treating HCC. Due to the natural drug resistance of chemoradiotherapy and targeted drugs, satisfactory results have not been achieved in terms of therapeutic efficacy and cost. AMP-Activated Protein Kinase (AMPK) is a serine/threonine protein kinase. It mainly coordinates the metabolism and transformation of energy between cells, which maintaining a balance between energy supply and demand. The processes of cell growth, proliferation, autophagy, and survival all involve various reaction of cells to energy changes. The regulatory role of AMPK in cellular energy metabolism plays an important role in the occurrence, development, treatment, and prognosis of HCC. Here, we reviewed the latest progress on the regulatory role of AMPK in the occurrence and development of HCC. Firstly, the molecular structure and activation mechanism of AMPK were introduced. Secondly, the emerging regulator related to AMPK and tumors were elaborated. Next, the multitasking roles of AMPK in the occurrence and development mechanism of HCC were discussed separately. Finally, the translational implications and the challenges of AMPK-targeted therapies for HCC treatment were elaborated. In summary, these pieces of information suggest that AMPK can serve as a promising specific therapeutic target for the treatment of HCC.

Magnetothermal-activated gene editing strategy for enhanced tumor cell apoptosis.

Precise and effective initiation of the apoptotic mechanism in tumor cells is one of the most promising approaches for the treatment of solid tumors. However, current techniques such as high-temperature ablation or gene editing suffer from the risk of damage to adjacent normal tissues. This study proposes a magnetothermal-induced CRISPR-Cas9 gene editing system for the targeted knockout of HSP70 and BCL2 genes, thereby enhancing tumor cell apoptosis. The magnetothermal nanoparticulate platform is composed of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles and the modified polyethyleneimine (PEI) and hyaluronic acid (HA) on the surface, on which plasmid DNA can be effectively loaded. Under the induction of a controllable alternating magnetic field, the mild magnetothermal effect (42℃) not only triggers dual-genome editing to disrupt the apoptosis resistance mechanism of tumor cells but also sensitizes tumor cells to apoptosis through the heat effect itself, achieving a synergistic therapeutic effect. This strategy can precisely regulate the activation of the CRISPR-Cas9 system for tumor cell apoptosis without inducing significant damage to healthy tissues, thus providing a new avenue for cancer treatment.

Identification of immune- and oxidative stress-related signature genes as potential targets for mRNA vaccines for pancreatic cancer patients.

Adenocarcinoma of the pancreas (PAAD) is one of the deadliest malignant tumors, and messenger ribonucleic acid vaccines, which constitute the latest generation of vaccine technology, are expected to lead to new ideas for the treatment of pancreatic cancer. The Cancer Genome Atlas-PAAD and Genotype-Tissue Expression data were merged and analyzed. Weighted gene coexpression network analysis was used to identify gene modules associated with tumor mutational burden among the genes related to both immunity and oxidative stress. Differentially expressed immune-related oxidative stress genes were screened via univariate Cox regression analysis, and these genes were analyzed via nonnegative matrix factorization. After immune infiltration analysis, least absolute shrinkage and selection operator regression combined with Cox regression was used to construct the model, and the usefulness of the model was predicted based on the receiver operating characteristic curve and decision curve analysis curves after model construction. Finally, metabolic pathway enrichment was analyzed using gene set enrichment analysis combined with Kyoto Encyclopedia of Genes and Genomes and gene ontology biological process analyses. This model consisting of the ERAP2, mesenchymal-epithelial transition factor (MET), CXCL9, and angiotensinogen (AGT) genes can be used to help predict the prognosis of pancreatic cancer patients more accurately than existing models. ERAP2 is involved in immune activation and is important in cancer immune evasion. MET binds to hepatocyte growth factor, leading to the dimerization and phosphorylation of c-MET. This activates various signaling pathways, including MAPK and PI3K, to regulate the proliferation, invasion, and migration of cancer cells. CXCL9 overexpression is associated with a poor patient prognosis and reduces the number of CD8 + cytotoxic T lymphocytes in the PAAD tumor microenvironment. AGT is cleaved by the renin enzyme to produce angiotensin 1, and AGT-converting enzyme cleaves angiotensin 1 to produce angiotensin 2. Exposure to AGT-converting enzyme inhibitors after pancreatic cancer diagnosis is associated with improved survival. The 4 genes identified in the present study - ERAP2, MET, CXCL9, and AGT - are expected to serve as targets for messenger ribonucleic acid vaccine development and need to be further investigated in depth.

Synergistic degradation of 2,4-dichlorophenoxyacetic acid in water by interfacial pre-reduction enhanced peroxymonosulfate activation derived from novel zero-valent iron/biochar.

Iron-based biochar exhibits great potential in degrading emerging pollutants and remediation of water environments. In this study, a highly efficient catalytic Fe0/biochar (MZB-800) was synthesized by the co-pyrolysis of poplar sawdust and K2FeO4 at 800 °C. A novel water purification technology of pre-reduction followed by PMS activation for MZB-800 was proposed to degrade the refractory 2,4-dichlorophenoxyacetic acid (2,4-D) pesticide. The corrosive effect of the strong oxidizing potassium salt endowed the MZB-800 surface with more Fe0 and porous structure, achieving greater 2,4-D adsorption binding energy. The removal efficiency of MZB-800 on 2,4-D was greater than that of biochar (BC) and conventional Fe0/biochar (Fe-BC) prepared by FeCl3·6 H2O as the precursor. The proposed novel water purification technology showed the synergistic effect between the interfacial pre-reduction and the PMS activation derived by MZB-800. Regarding 2,4-D degradation and dechlorination performance, the synergistic coefficient between pre-reduction and subsequent PMS activation for MZB-800 were 2 and 1.4 respectively. Based on the normalized kinetic analysis and the Langmuir-Hinshelwood model, we proposed the underlying mechanism of MZB-800 interfacial pre-reduction and subsequent PMS activation for synergistic removal of 2,4-D. The large amount of Fe2+ and hydroxyl density accumulated by the Fe0 and hydroquinone structures on the MZB-800 surface during the pre-reduction stage provided abundant active sites for the subsequent activation of PMS. The improved activation reaction rate generated more reactive oxygen species, further strengthening the removal efficiency of 2,4-D. This work manifested that the novel water purification technology of pre-reduction/PMS activation of iron-based biochar is feasible for removing emerging pollutants in the water environment. ENVIRONMENTAL IMPLICATION: Extensive abuse of 2,4-dichlorophenoxyacetic acid (2,4-D) herbicide with high solubility and refractory degradation has caused environmental pollution and ecological deterioration. This manuscript described a novel water purification technology, centered on high-efficiency Fe0/biochar and utilizing pre-reduction and PMS reactivation strategies to synergistically degrade 2,4-D, which had strong environmental relevance. By elucidating the synergistic removal mechanism, the research provided valuable insights into removing emerging pollutants, thus promoting environmental sustainability and safeguarding ecosystem health. Overall, it is of high importance to provide a feasible and efficient method for removing hazardous 2,4-D from water environments, which contributes to addressing pressing environmental problems.

Nanocatalytic Anti-Tumor Immune Regulation.

Immunotherapy has brought a new dawn for human being to defeat cancer. Although existing immunotherapy regimens (CAR-T, etc.) have made breakthroughs in the treatments of hematological cancer and few solid tumors such as melanoma, the therapeutic efficacy on most solid tumors is still far from being satisfactory. In recent years, the researches on tumor immunotherapy based on nanocatalytic materials are under rapid development, and significant progresses have been made. Nanocatalytic medicine has been demonstrated to be capable of overcoming the limitations of current clinicnal treatments by using toxic chemodrugs, and exhibits highly attractive advantages over traditional therapies, such as the enhanced and sustained therapeutic efficacy based on the durable catalytic activity, remarkably reduced harmful side-effects without using traditional toxic chemodrugs, and so on. Most recently, nanocatalytic medicine has been introduced in the immune-regulation for disease treatments, especially, in the immunoactivation for tumor therapies. This article presents the most recent progresses in immune-response activations by nanocatalytic medicine-initiated chemical reactions for tumor immunotherapy, and elucidates the mechanism of nanocatalytic medicines in regulating anti-tumor immunity. By reviewing the current research progress in the emerging field, this review will further highlight the great potential and broad prospects of nanocatalysis-based anti-tumor immune-therapeutics.

Identification of a 2-phenylthiazole derivative acetylcholinesterase modulator with in vitro antitumor activity in breast cancer cells.

Acetylcholinesterase (AchE) is a serine hydrolase with classical function to degrade acetylcholine and terminate neurotransmission. While "nonclassical" functions of AchE were involved in cell growth, death, invasion, etc. The expression and activity of AchE is changed in tumors, suggesting AChE inhibitors (AchEIs) may serve as potential antitumor drugs. In this study, the antitumor activity of a series of 2-phenylthiazole derivatives originally designed and synthesized as AchEIs were investigated. One compound named A6, was screened out with superior antitumor efficacy, especially against breast cancer MCF-7 cells. A6 significantly disrupted the amino acid metabolism and inhibited migration of MCF-7. In addition, A6 induced apoptosis of MCF-7 cells. To clarify how A6 affected on MCF-7 cells, RNA-seq analysis was conducted to evaluate the whole genome effect of A6 on gene expression. A total of 153 genes were increased, and the expression of 81 genes was decreased. GO and KEGG enrichment analysis showed A6 treatment mainly disrupted sterol/cholesterol pathway, Ras signaling pathway, VEGF signaling pathway, etc. Moreover, bioinformatic analysis and cell viability test showed A6 plays anticancer role by regulating Best1 and HIST1H2BJ. These results indicate that AchEI A6 could be a potential antitumor agent for breast cancer patients and could help the development of novel therapies.

Effects of Temperature, Metal Ions and Biosurfactants on Interaction Mechanism between Caffeic Acid Phenethyl Ester and Hemoglobin.

Caffeic acid phenylethyl ester (CAPE) is a natural polyphenol extracted from propolis, which is reported to have several pharmacological effects such as antibacterial, antitumor, antioxidant and anti-inflammatory activities. Hemoglobin (Hb) is closely related to the transport of drugs, and some drugs, including CAPE, can lead to a change in Hb concentration. Herein, the effects of temperature, metal ions and biosurfactants on the interaction between CAPE and Hb were studied using ultraviolet-visible spectroscopy (UV-Vis), fluorescence spectroscopy, circular dichroism (CD), dynamic light scattering (DLS) and molecular docking analysis. The results showed that the addition of CAPE led to changes in the microenvironment of Hb amino acid residues as well as the secondary structure of Hb. Hydrogen bonding and van der Waals force were found to be the main driving forces for the interaction between CAPE and Hb through fluorescence spectroscopy and thermodynamic parameter data. The results of fluorescence spectroscopy also showed that lowering the temperature, adding biosurfactants (sodium cholate (NaC) and sodium deoxycholate (NaDC)) and the presence of Cu2+ increased the binding force between CAPE and Hb. These results provide useful data for the targeted delivery and absorption of CAPE and other drugs.

Identifying key transcription factors and miRNAs coregulatory networks associated with immune infiltrations and drug interactions in idiopathic pulmonary arterial hypertension.

BACKGROUND: The deregulated genetic factors are critically associated with idiopathic pulmonary arterial hypertension (IPAH) development and progression. However, the identification of hub-transcription factors (TFs) and miRNA-hub-TFs co-regulatory network-mediated pathogenesis in IPAH remains lacking. METHODS: We used GSE48149, GSE113439, GSE117261, GSE33463, and GSE67597 for identifying key genes and miRNAs in IPAH. We used a series of bioinformatics approaches, including R packages, protein-protein interaction (PPI) network, and gene set enrichment analysis (GSEA) to identify the hub-TFs and miRNA-hub-TFs co-regulatory networks in IPAH. Also, we employed a molecular docking approach to evaluate the potential protein-drug interactions. RESULTS: We found that 14 TFs encoding genes, including ZNF83, STAT1, NFE2L3, and SMARCA2 are upregulated, and 47 TFs encoding genes, including NCOR2, FOXA2, NFE2, and IRF5 are downregulated in IPAH relative to the control. Then, we identified the differentially expressed 22 hub-TFs encoding genes, including four upregulated (STAT1, OPTN, STAT4, and SMARCA2) and 18 downregulated (such as NCOR2, IRF5, IRF2, MAFB, MAFG, and MAF) TFs encoding genes in IPAH. The deregulated hub-TFs regulate the immune system, cellular transcriptional signaling, and cell cycle regulatory pathways. Moreover, the identified differentially expressed miRNAs (DEmiRs) are involved in the co-regulatory network with hub-TFs. The six hub-TFs encoding genes, including STAT1, MAF, CEBPB, MAFB, NCOR2, and MAFG are consistently differentially expressed in the peripheral blood mononuclear cells of IPAH patients, and these hub-TFs showed significant diagnostic efficacy in distinguishing IPAH cases from the healthy individuals. Moreover, we revealed that the co-regulatory hub-TFs encoding genes are correlated with the infiltrations of various immune signatures, including CD4 regulatory T cells, immature B cells, macrophages, MDSCs, monocytes, Tfh cells, and Th1 cells. Finally, we discovered that the protein product of STAT1 and NCOR2 interacts with several drugs with appropriate binding affinity. CONCLUSIONS: The identification of hub-TFs and miRNA-hub-TFs co-regulatory networks may provide a new avenue into the mechanism of IPAH development and pathogenesis.

LncRNA DDX11-AS1 Promotes Chemoresistance through LIN28A-Mediated ATG12 mRNA Stabilization in Breast Cancer.

INTRODUCTION: During breast cancer chemotherapy, the chemoresistance that frequently accompanies the treatment has become a big challenge. Long noncoding RNAs (LncRNAs) have been related to the development of chemoresistance in multiple cancer types. LncRNA DDX11-AS1 has shown a carcinogenic role in lung and colorectal cancer and was reported to enhance oxaliplatin resistance in gastric cancer and Taxol insensitivity in esophageal cancer. But its role in breast cancer chemotherapy drug resistance remains unknown. This study aimed to investigate the function and mechanism of lncRNA DDX11-AS1 in breast cancer chemoresistance. METHODS: The relationship between DDX11-AS1 and adriamycin (ADR) resistance was confirmed by qPCR, cell viability tests, and survival analysis. Then, RNA immunoprecipitation was conducted to evaluate the interaction between DDX11-AS1 and RNA-binding protein LIN28A. The regulation effect of LIN28A on autophagy-related genes ATG7 or ATG12 was detected by RNA stability assay and Western blot. Their correlation analysis was evaluated in GEO datasets and further validated by immunohistochemical results. The clinical significance of DDX11-AS1, ATG7, or ATG12 was evaluated by Kaplan-Meier Plotter analysis. RESULTS: Here, we reported DDX11-AS1 was significantly upregulated in chemoresistant breast cancer cells and overexpression of DDX11-AS1 promoted ADR resistance in breast cancer. LIN28A could interact with DDX11-AS1 and was involved in DDX11-AS1-mediated ADR resistance. Interfering with LIN28A reversed DDX11-AS1-induced ADR resistance. LIN28A could increase the protein level of ATG7 and ATG12 by increasing their mRNA stability. Survival analysis showed that ATG12 expression level was negatively correlated with the prognosis of breast cancer patients. CONCLUSION: This study clarifies the role of DDX11-AS1 in breast cancer chemoresistance and revealed a new mechanism, that is, interacting with LIN28A to stabilize ATG7 and ATG12 and jointly promote chemorefractory. These findings warrant further in vivo investigations to study DDX11-AS1 as a potential target to overcome chemoresistance.

Effects of different antioxidants combined with high hydrostatic pressure on the color and anthocyanin retention of a blueberry juice blend during storage.

Blueberry juice has been found to undergo severe browning after treatment and cold storage, such as processing by high hydrostatic pressure (HHP) at 550 MPa/10 min/25 °C followed storage at 4 °C for 4 days. This browning may be due to the degradation of anthocyanin (AC) in the berries. Therefore, in this study, gallic acid (GA), ferulic acid (FA), ascorbic acid (VC), citric acid (CA), tea polyphenol (TP) and α-tocopherol (VE) were compared to determine their ability to improve the stability of the AC in HHP-treated blueberry juice. The juice was combined with the six abovementioned antioxidants at different concentrations, then treated by HHP at 550 MPa/10 min/25 °C and stored at 4 °C for 20 days. Thereafter, the pH levels, degrees °Brix, color parameters, total AC content and polyphenol oxidase (PPO) activity of the blueberry juice blend were measured and compared. Gallic acid at 2 g/L was found to be the most effective antioxidant to protect against AC degradation. After storage at 4 °C for 20 days, the AC content of the juice with no added antioxidants had decreased by 62.27% with a PPO relative activity of 50.78%, while the AC content of juice supplemented with 2 g/L GA had decreased by 13.42% with a PPO relative activity of 28.13%. The results of this study, thus, suggest that GA can stabilize the structure of AC in blueberry juice and reduce PPO activity, which may be beneficial in guiding the production of blueberry juice with high AC retention.

[Effects of Water Management on the Transformation of Iron Oxide Forms in Paddy Soils and Its Coupling with Changes in Cadmium Activity].

The transformation of iron oxide forms in the process of soil water management in paddy fields has an important impact on soil cadmium (Cd) activity and accumulation in rice. The test soil for this experiment was purple paddy soil in southwest China contaminated with exogenously added Cd. Through indoor cultivation experiments, the effects of water management (continuous flooding, CW; alternating wet and dry, DW) combined with iron oxide application (goethite, G-Fe; iron powder, Fe) on the pH, redox state (Eh, pe+pH), iron oxide form conversion, and Cd bioavailability changes in Cd-contaminated soil were studied. Meanwhile, the coupling relationship between the transformation of iron oxide form and the evolution of soil Cd activity driven by water management were also analyzed. The results showed that DTPA-Cd content was decreased by 17.7%-39.2% after 93 days of flooding, indicating that CW could significantly reduce soil Cd bioavailability. CW combined with Fe or G-Fe application significantly enhanced the passivating effect on soil Cd. Among them, the DTPA-Cd content of G-Fe application was reduced by 24.3% compared with that of the CK after 14 d of flooding; thus, G-Fe was effective in short-term passivation. The reduction in DTPA-Cd content of Fe application was 39.2% after 93 d of flooding, so Fe was able to passivate soil Cd continuously. It was also found that the application of iron oxides under alternating wet and dry conditions had no passivating effect on soil Cd. Furthermore, based on correlation analysis, the formation of amorphous iron (Feo) (P<0.01) was verified as the main reason for the change in Cd bioavailability of Cd in the soil:firstly, the soil pH gradually declined to 7.4, and the soil was kept at reduction conditions under CW, which promoted the morphology transformation from the crystalline state (Fec) to Feo. This transformation subsequently pushed the Cd transformation from the exchangeable state to the iron-manganese combined state and thus resulted in the significant decrease in Cd bioavailability. Meanwhile, the content and proportion of Feo were also significantly increased by the application of CW combined with Fe or G-Fe, thus further enhancing its Cd passivating effect on the soil. This research provides a scientific basis for the optimal water management and the application of iron-containing passivation agent in the safe use of Cd-contaminated paddy soils.

Cationic liposomes co-deliver chemotherapeutics and siRNA for the treatment of breast cancer.

In order to improve the targeting efficiency and reduce anti-breast cancer therapeutic side effects, paclitaxel (PTX), crizotinib (CRI), and Bcl-xL siRNA were co-loaded in cationic liposomes (CTL), which exhibited a substantial enhanced permeability and retention effect (EPR effect) in breast cancer. CTL containing crizotinib and paclitaxel (CRI-PTX-CTL) had particle sizes of (138.63 ± 1.53) nm and zeta potentials of (50.90 ± 0.30) mV, respectively. It was spherical and uniformly dispersed under TEM. The in vitro release of CRI-PTX-CTL showed that the cumulative release rates of CRI and PTX within 12 h were 64.37% and 54.71%, and released from liposomes at the same time. At the cellular level, CRI and PTX were discovered to have synergistic effects. Cell uptake experiments demonstrated that CRI, PTX, and siRNA contained in CTL can be effectively taken up by MCF-7 cells. It was further proved that CTL-siRNA could effectively inhibit the expression of Bcl-xL in cells. CRI, PTX and Bcl-xL siRNA delivered by CTL showed enhanced cytotoxicity during in vitro experiments. Therefore, this study proved that the CRI-PTX-CTL-siRNA was a very promising delivery system for the treatment of breast cancer.

Co-delivery of F7 and crizotinib by thermosensitive liposome for breast cancer treatment.

In order to enhance the targeting efficiency and reduce the side effects and drug resistance, crizotinib (Cri) and F7 were co-loaded in a thermosensitive liposome (TSL) (F7-Cri-TSL), which showed enhanced permeability and retention in breast cancer model, as well as local controlled release by external hyperthermia. Cri is an inhibitor for cell proliferation and a promoter of apoptosis, by inhibiting the phosphorylation of intracellular ALK and c-Met, but its drug resistance limits its application. F7 is a novel drug candidate with significant resistance to cyclin-dependent kinase, but its use was restricted by its high toxicity. The F7-Cri-TSL was found with excellent particle size (about 108 nm), high entrapment efficiency (>95%), significant thermosensitive property, and good stability. Furthermore, F7-Cri-TSL/H had strongest cell lethality compared with other formulations. On the MCF-7 xenograft mice model, the F7-Cri-TSL also exhibited therapeutic synergism of Cri, F7 and hyperthermia. Meanwhile, it was shown that the TSL reduced the systemic toxicity of the chemotherapy drug. Therefore, the F7-Cri-TSL may serve as a promising system for temperature triggered breast cancer treatment.

The nano delivery systems and applications of mRNA.

The current COVID-19 epidemic has greatly accelerated the application of mRNA technology to our real world, and during this battle mRNA has proven it's unique advantages compared to traditional biopharmaceutical and vaccine technology. In order to overcome mRNA instability in human physiological environments, mRNA chemical modifications and nano delivery systems are two key factors for their in vivo applications. In this review, we would like to summarize the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in innovative materials and delivery strategies. The nano delivery systems include lipid delivery systems (lipid nanoparticles and liposomes), polymer complexes, micelles, cationic peptides and so on. The similarities and differences of lipid nanoparticles and liposomes are also discussed. In addition, this review also present the applications of mRNA to other areas than COVID-19 vaccine, such as infectious diseases, tumors, and cardiovascular disease, for which a variety of candidate vaccines or drugs have entered clinical trials. Furthermore, mRNA was found that it might be used to treat some genetic disease, overcome the immaturity of the immune system due to the small fetal size in utero, treat some neurological diseases that are difficult to be treated surgically, even be used in advancing the translation of iPSC technology et al. In short, mRNA has a wide range of applications, and its era has just begun.

Vincristine-doxorubicin co-loaded artificial low-density lipoproteins towards solid tumours.

To construct an artificial low-density lipoprotein (aLDL) that highly mimics low-density lipoprotein (LDL) in vivo, and deliver vincristine (VCR) - doxorubicin (DOX) simultaneously, the 100 nm and 35 nm DOX-VCR-aLDLs (DV-aLDLs) were constructed, then the physicochemical characteristics were evaluated. Through in vitro inverse gravity diffusion experiment, the tumour cake and sphere model experiment, draw a conclusion that the diffusion of 35 nm DV-aLDLs was stronger than 100 nm DV-aLDLs, and the tumour retention of 35 nm DV-aLDLs was better than the DV-solution. In addition, the three-dimension (3D) in vivo distribution imaging of aLDLs was performed on HepG-2 tumour-bearing nude mice, followed by the biodistribution and therapeutic efficacy on these xenograft models. Taking advantage of better diffusion capacity in tumour tissue, as well as the synergistic effect of VCR and DOX, the 35 nm DV-aLDL had the strongest efficacy and the lowest toxicity. High entrapment efficiency and stability, both active and passive targeting, making aLDL a potential carrier for tumour-targeted therapy at the same time.

Dynamic landscape mapping of humoral immunity to SARS-CoV-2 identifies non-structural protein antibodies associated with the survival of critical COVID-19 patients.

A comprehensive analysis of the humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential in understanding COVID-19 pathogenesis and developing antibody-based diagnostics and therapy. In this work, we performed a longitudinal analysis of antibody responses to SARS-CoV-2 proteins in 104 serum samples from 49 critical COVID-19 patients using a peptide-based SARS-CoV-2 proteome microarray. Our data show that the binding epitopes of IgM and IgG antibodies differ across SARS-CoV-2 proteins and even within the same protein. Moreover, most IgM and IgG epitopes are located within nonstructural proteins (nsps), which are critical in inactivating the host's innate immune response and enabling SARS-CoV-2 replication, transcription, and polyprotein processing. IgM antibodies are associated with a good prognosis and target nsp3 and nsp5 proteases, whereas IgG antibodies are associated with high mortality and target structural proteins (Nucleocapsid, Spike, ORF3a). The epitopes targeted by antibodies in patients with a high mortality rate were further validated using an independent serum cohort (n = 56) and using global correlation mapping analysis with the clinical variables that are associated with COVID-19 severity. Our data provide fundamental insight into humoral immunity during SARS-CoV-2 infection. SARS-CoV-2 immunogenic epitopes identified in this work could also help direct antibody-based COVID-19 treatment and triage patients.

Epidemiology of norovirus gastroenteritis in hospitalized children under five years old in western China, 2015-2019.

OBJECTIVES: Norovirus is associated with one-fifth of all gastroenteritis cases, but basic epidemiological data is lacking, especially in developing countries. As long-term surveillance on norovirus gastroenteritis is scarce in western China, this study aims to update the epidemiological knowledge of norovirus gastroenteritis and to characterize the genotypes of norovirus strains. METHODS: Stool samples were collected from hospitalized children under 5 years old with gastroenteritis in Chengdu, China. All samples were tested for norovirus as well as rotavirus, sapovirus, enteric adenovirus, and astrovirus by real-time RT-PCR. RdRp and VP1 genes were sequenced in norovirus-positive samples to investigate viral phylogenies. RESULTS: Of the 1181 samples collected from 2015 to 2019, 242 (20.5%) were positive for norovirus. Among norovirus-positive cases, 65 cases had co-infection with another virus; norovirus/enteric adenovirus was most frequently detected (50.8%, 33/65). The highest positive rate was observed in children aged 13-18 months (23.7%, 68/287). Norovirus infection peaked in autumn (36.6%, 91/249), followed by summer (20.3%, 70/345). Pearson correlation analysis showed significant correlation between the norovirus-positive rate and humidity (r = 0.773, P < 0.05). GII.4 Sydney 2012 [P31] (48.5%, 79/163) and GII.3 [P12] (35.6%, 58/163) were the dominant norovirus strains. CONCLUSIONS: Norovirus has become one of the most common causes of viral gastroenteritis in children under 5 years old in western China. Continuous monitoring is imperative for predicting the emergence of new epidemic strains and for current vaccine development.

Exosomes from different cells: Characteristics, modifications, and therapeutic applications.

Exosomes are cystic vesicles secreted by living cells with a phospholipid bilayer membrane. Importantly, these vesicles could serve to carry lipids, proteins, genetic materials, and transmit biological information in vivo. The cell-specific proteins and genetic materials in exosomes are capable of reflecting their cell origin and physiological status. Based on the different tissues and cells (macrophage, dendritic cells, tumor cells, mesenchymal stem cells, various body fluids, and so on), exosomes exhibit different characteristics and functions. Furthermore, owing to their high delivery efficiency, biocompatibility, and multifunctional properties, exosomes are expected to become a new means of drug delivery, disease diagnosis, immunotherapy, and precise treatment. At the same time, in order to supplement or enhance the therapeutic applicability of exosomes, chemical or biological modifications can be used to broaden, change or improve their therapeutic capabilities. This review focuses on three aspects: the characteristics and original functions of exosomes secreted by different cells, the modification and transformation of exosomes, and the application of exosomes in different diseases.

F7 and topotecan co-loaded thermosensitive liposome as a nano-drug delivery system for tumor hyperthermia.

In order to enhance the targeting efficiency and reduce anti-tumor drug's side effects, topotecan (TPT) and F7 were co-loaded in thermosensitive liposomes (F7-TPT-TSL), which show enhanced permeability and retention in tumors, as well as local controlled release by heating in vitro. TPT is a water-soluble inhibitor of topoisomerase I that is converted to an inactive carboxylate structure under physiological conditions (pH 7.4). F7 is a novel drug significantly resistant to cyclin-dependent kinase but its use was restricted by its high toxicity. F7-TPT-TSL had excellent particle distribution (about 103 nm), high entrapment efficiency (>95%), obvious thermosensitive property, and good stability. Confocal microscopy demonstrated specific higher accumulation of TSL in tumor cells. MTT proved F7-TPT-TSL/H had strongest cell lethality compared with other formulations. Then therapeutic efficacy revealed synergism of TPT and F7 co-loaded in TSL, together with hyperthermia. Therefore, the F7-TPT-TSL may serve as a promising system for temperature triggered cancer treatment.

Phylogenetic analysis of clinical strains of Helicobacter pylori isolated from patients with gastric diseases in Tibet.

BACKGROUND: Helicobacter pylori (H. pylori) is a Gram-negative pathogenic bacterium that causes chronic gastritis and other gastric diseases in humans. In Tibet, China, the infection of H. pylori is an important risk factor that caused gastric cancer. METHODS: To understand the characteristics of this pathogen in Tibet, five strains of H. pylori were isolated from three patients' oral cavity or stomach who had either a gastric ulcer or gastritis. We performed genome sequences of these five clinical strains on Illumina Hiseq, and 55,016-63666 SNVs/InDels were identified by comparing to the reference strain of H. pylori 26995. RESULTS: The phylogenetic analysis with multi-locus sequence typing (MLST) showed that five Tibetan strains were defined as hpEurope population and their proteins encoded by the cagA gene also presented a western type. Also, the strains that were isolated from the same patients' oral cavity and stomach exhibited homology in molecular evolution. CONCLUSIONS: This is the first study to investigate the phylogenetic population structure of the epidemic strains of H. pylori in Tibet, which may improve cognition of Tibetan strains and confirm the homology of the strains from oral cavity and stomach.