Dual biomarkers-activatable hollow MnO2-Based theranostic nanoplatform for efficient breast cancer-specific multisite fluorescence imaging and synergistic therapy.

BACKGROUND: Theranostic nanoplatforms with integrated diagnostic imaging and multiple therapeutic functions play a vital role in precise diagnosis and efficient treatment for breast cancer, but unfortunately, these nanoplatforms are usually stuck in single-site imaging and single mode of treatment, causing unsatisfactory diagnostic and therapeutic efficiency. Herein, a dual biomarkers-activatable facile hollow mesoporous MnO2 (H-MnO2)-based theranostic nanoplatform, DNAzyme@H-MnO2-MUC1 aptamer (DHMM), was constructed for the simultaneous multi-site diagnosis and multiple treatment of breast cancer. RESULTS: The DHMM acted as an integrated diagnostic and therapeutic nanoplatform that realizes multi-site fluorescence imaging-guided high-efficient photothermal/chemodynamic/gene synergistic therapy (PTT/CDT/GT) for breast cancer. The H-MnO2 exhibits high loading capacity for Cy5-MUC1 aptamer (3.05 pmoL µg-1) and FAM-DNAzyme (3.37 pmoL µg-1), and excellent quenching for the probes. In the presence of MUC1 on the cell membrane and GSH in the cytoplasm, Cy5-MUC1 aptamer and FAM-DNAzyme was activated triggering dual-channel fluorescence imaging at different sites. Moreover, the self-supplied Mn2+ was further supplied as DNAzyme cofactors to catalytic cleavage intracellular EGR-1 mRNA for high-efficient GT and stimulated the Fenton-like reaction for CDT. The H-MnO2 also showcases a favorable photothermal performance with a photothermal conversion efficiency of 44.16%, which ultimately contributes to multi-site fluorescence imaging-guided synergistic treatment with an apoptosis rate of 71.82%. SIGNIFICANCE: This dual biomarker-activatable multiple therapeutic nanoplatform was realized multi-site fluorescence imaging-guided PTT/CDT/GT combination therapy for breast cancer with higher specificity and efficiency, which provides a promising theranostic nanoplatform for the precision and efficiency of breast cancer treatment.

Safe Farming: Ultrafine Bubble Water Reduces Insect Infestation and Improves Melon Yield and Quality.

Melon pest management relies on the excessive application of pesticides. Reducing pesticide spraying has become a global issue for environmental sustainability and human health. Therefore, developing a new cropping system that is sustainable and eco-friendly is important. This study found that melon seedlings irrigated with ultrafine water containing H2 and O2 (UFW) produced more root hairs, increased shoot height, and produced more flowers than the control irrigated with reverse osmosis (RO) water. Surprisingly, we also discovered that UFW irrigation significantly reduced aphid infestation in melons. Based on cryo-scanning electron microscope (cryo-SEM) observations, UFW treatment enhanced trichome development and prevented aphid infestation. To investigate whether it was H2 or O2 that helped to deter insect infestation, we prepared UF water enrichment of H2 (UF+H2) and O2 (UF+O2) separately and irrigated melons. Cryo-SEM results indicated that both UF+H2 and UF+O2 can increase the density of trichomes in melon leaves and petioles. RT-qPCR showed that UF+H2 significantly increased the gene expression level of the trichome-related gene GLABRA2 (GL2). We planted melons in a plastic greenhouse and irrigated them with ultrafine water enrichment of hydrogen (UF+H2) and oxygen (UF+O2). The SPAD value, photosynthetic parameters, root weight, fruit weight, and fruit sweetness were all better than the control without ultrafine water irrigation. UFW significantly increased trichome development, enhanced insect resistance, and improved fruit traits. This system thus provides useful water management for pest control and sustainable agricultural production.

Critical Roles of Acidic Residues in Loop Regions of the Structural Surface for the Salt Tolerance of a GH39 ß-d-Xylosidase.

Xylan is the main component of hemicellulose. Complete hydrolysis of xylan requires synergistically acting xylanases, such as ß-d-xylosidases. Salt-tolerant ß-d-xylosidases have significant application benefits, but few reports have explored the critical amino acids affecting the salt tolerance of xylosidases. Herein, the site-directed mutation was used to demonstrate that negative electrostatic potentials generated by 19 acidic residues in the loop regions of the structural surface positively correlated with the improved salt tolerance of GH39 ß-d-xylosidase JB13GH39P28. These mutants showed reduced negative potentials on structural surfaces as well as a 13-43% decrease in stability in 3.0-30.0% (w/v) NaCl. Six key residue sites, D201, D259, D297, D377, D395, and D474, were confirmed to influence both the stability and activity of GH39 ß-d-xylosidase. The activity of the GH39 ß-d-xylosidase was found promoting by SO42- and inhibiting by NO3-. Values of Km and Kcat/Km decreased aggravatedly in 30.0% (w/v) NaCl when mutation operated on residues E179 and D182 in the loop regions of the catalytic domain. Taken together, mutation on acidic residues in loop regions from catalytic and noncatalytic domains may cause the deformation of catalytic pocket and aggregation of protein particles then decrease the stability, binding affinity, and catalytic efficiency of the ß-d-xylosidase.

Neutrophils are involved in early bone formation during midpalatal expansion.

OBJECTIVE: Midpalatal expansion (MPE) is routinely employed to treat transverse maxillary arch deficiency. Neutrophils are indispensable for recruiting bone marrow stromal cells (BMSCs) at the initial stage of bone regeneration. This study aimed to explore whether neutrophils participate in MPE and how they function during bone formation under mechanical stretching. MATERIALS AND METHODS: The presence and phenotype of neutrophils in the midpalatal suture during expansion were detected by flow cytometry and immunofluorescence staining. The possible mechanism of neutrophil recruitment and polarization was explored in vitro by exposing vascular endothelial cells (VECs) to cyclic tensile strain. RESULTS: The number of neutrophils in the distracted suture peaked on Day 3, and N2-type neutrophils significantly increased on Day 5 after force application. The depletion of circulatory neutrophils reduced bone volume by 43.6% after 7-day expansion. The stretched VECs recruited neutrophils via a CXCR2 mechanism in vitro, which then promoted BMSC osteogenic differentiation through the VEGFA/VEGFR2 axis. Consistently, these neutrophils showed higher expression of canonical N2 phenotype genes, including CD206 and Arg1. CONCLUSIONS: These results suggested that neutrophils participated in early bone formation during MPE. Based on these findings, we propose that stretched VECs recruited and polarized neutrophils, which, in turn, induced BMSC osteogenic differentiation.

Decoding the multifaceted signatures and transcriptomic characteristics of stem cells derived from apical papilla and dental pulp of human supernumerary teeth.

Supernumerary teeth are advantaged sources for high-quality stem cell preparation from both apical papilla (SCAP-Ss) and dental pulp (DPSCs). However, the deficiency of the systematic and detailed comparison of the biological and transcriptomic characteristics of the aforementioned stem cells largely hinders their application in regenerative medicine. Herein, we collected supernumerary teeth for SCAP-S and DPSC isolation and identification by utilizing multiple biological tests (e.g., growth curve, cell cycle and apoptosis, adipogenic and osteogenic differentiation, and quantitative real-time polymerase chain reaction). Furthermore, we took advantage of transcriptome sequencing and multifaceted bioinformatic analyses to dissect the similarities and diversities between them. In this study, we found that SCAP-Ss and DPSCs showed indistinctive signatures in morphology and immunophenotypes, whereas with diversity in cell vitality and multi-lineage differentiation as well as gene expression profiling and differentially expressed genes-associated gene ontology and signaling pathways. Collectively, our data indicated the diversity of the multifaceted signatures of human supernumerary teeth-derived stem cells both at the cellular and molecular levels, which also supplied new references for SCAP-Ss serving as splendid alternative stem cell sources for regenerative medicine purposes.

Matrix mechanics regulate the polarization state of bone marrow-derived neutrophils through the JAK1/STAT3 signaling pathway.

Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less reactive oxygen species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE.

The novel HLA-DRB1*12:01:12 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DRB1*12:01:12 differs from HLA-DRB1*12:01:01:01 by one nucleotide in exon 2.

The novel HLA-C*01:239 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-C*01:239 differs from HLA-C*01:02:01:01 by one nucleotide in exon 4.

The novel HLA-DRB1*14:246 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DRB1*14:246 differs from HLA-DRB1*14:18 by one nucleotide in exon 2.

A DNA-Au nanomachine activated by dual types of biomarkers for multi-site imaging and gene silencing.

A programmed DNA-Au nanomachine has been constructed to achieve in situ imaging of transmembrane glycoprotein MUC1 and cytoplasmic miRNA-21 and trigger gene silencing therapy. The results of MCF-7 cell-specific imaging and apoptosis experiments demonstrate that the nanomachine provides a valuable nanotheranostic platform for accurate multi-site imaging and intracellular gene silencing.

Prepared carbon dots from wheat straw for detection of Cu2+ in cells and zebrafish and room temperature phosphorescent anti-counterfeiting.

The green synthesis of fluorescent carbon dots from biomass is critical for their sustainable application. Herein, using wheat straw as a single precursor, carbon dots (CDs) were prepared through a one-step carbonization process, and the obtained CDs have intense blue luminescence and excitation-independent photoluminescent behavior. The solution of CDs shows good biocompatibility, and low cytotoxicity successfully used as hopeful bioimaging and biosensing probe for Cu2+ in HepG2 cells and zebrafish. Based on CDs, boron-doped carbon dots with IPA shells (CDs@IPA) can be obtained by doping boron element and isophthalic acid (IPA) coating. CDs@IPA irradiated with different wavelength ultraviolet lamps shows different solid fluorescence, while turning off the ultraviolet lamp can produce green visible room temperature phosphorescence (RTP) to the naked eyes for 5 s. The two kinds of wheat straw-based carbon dots have bifunctional luminescence properties and can be used to detect Cu2+ and serve as RTP anti-counterfeiting signs to ensure information security.

"HLA-10-SNP": A new qPCR-based system for rapid, effective, and accurate detection of 10 important SNPs in the HLA region.

Mastering the SNP content in the HLA region can be based on it to judiciously select unrelated donor stem cells with preferable MHC matching to lower postoperative complications. Herein, quantitative PCR-based primers and probes were designed for 10 transplants outcome-associated SNP loci with two-allelic polymorphism, and then a new detection system ("HLA-10-SNP") was established. Compared with Sanger sequencing, its accuracy has been proven to reach 100%. Additionally, fluorescent PCR typing of 10 important SNPs via this system expressed excellent repeatability (sensitivity, 20 ng). Overall, the new system achieves single-sample classification precision and easily distinguishable results, equipped with the advantages of simple, rapid, accurate, and effective, promising to acquire widespread popularization and application in clinical settings.

Poria cum Radix Pini Rescues Barium Chloride-Induced Arrhythmia by Regulating the cGMP-PKG Signalling Pathway Involving ADORA1 in Zebrafish.

The traditional Chinese medicine Poria cum Radix Pini (PRP) is a fungal medicinal material that has been proven to play an important role in the treatment of arrhythmia. However, the mechanism of its effect on arrhythmia is still unclear. In this study, network pharmacology and metabolomics correlation analysis methods were used to determine the key targets, metabolites and potential pathways involved in the effects of PRP on arrhythmia. The results showed that PRP can significantly improve cardiac congestion, shorten the SV-BA interval and reduce the apoptosis of myocardial cells induced by barium chloride in zebrafish. By upregulating the expression of the ADORA1 protein and the levels of adenosine and cGMP metabolites in the cGMP-PKG signalling pathway, PRP can participate in ameliorating arrhythmia. Therefore, we believe that PRP shows great potential for the treatment of arrhythmia.

Distribution of killer cell immunoglobulin-like receptor (KIR) genes in a large, multi-centre cohort of Chinese donors.

BACKGROUND: The killer cell immunoglobulin-like receptor (KIR), which mediates the killing function of NK cells, is an attractive candidate for adoptive cellular therapy. The ethnic distribution for China provides a unique opportunity to investigate KIR gene distribution. AIM: The aim of this study was to explore the relationship between population history and the rapidly evolving KIR genetic diversity. SUBJECTS AND METHODS: 8050 Chinese donors from 184 hospitals were included to analyse frequency, haplotype, and B-content data of 16 KIR genes, by PCR-SSP for KIR genotyping. RESULTS: KIR gene carrier frequencies were found similar to those observed in other studies on Han, but different from Thais, Japanese, Africans, and populations of West Eurasian ancestry. High-frequency KIR genotype profiles found in the present population were consistent with other studies on Han populations but different from those conducted on other cohorts. The majority of our cohort carried group A KIR gene motifs. Additionally, populations with similar geographic locations in China were shown clustered together, while Hainan and Xinjiang provinces were slightly separated from these. CONCLUSION: The distribution of KIR genes varies by geographic region, and different ethnic groups may be a confounding factor of KIR diversity.

Hypericum perforatum L. Regulates Glutathione Redox Stress and Normalizes Ggt1/Anpep Signaling to Alleviate OVX-Induced Kidney Dysfunction.

Menopause and associated renal complications are linked to systemic redox stress, and the causal factors remain unclear. As the role of Hypericum perforatum L. (HPL) in menopause-induced kidney disease therapy is still ambiguous, we aim to explore the effects of HPL on systemic redox stress under ovariectomy (OVX)-induced kidney dysfunction conditions. Here, using combined proteomic and metabolomic approaches, we constructed a multi-scaled "HPL-disease-gene-metabolite" network to generate a therapeutic "big picture" that indicated an important link between glutathione redox stress and kidney impairment. HPL exhibited the potential to maintain cellular redox homeostasis by inhibiting gamma-glutamyltransferase 1 (Ggt1) overexpression, along with promoting the efflux of accumulated toxic amino acids and their metabolites. Moreover, HPL restored alanyl-aminopeptidase (Anpep) expression and metabolite shifts, promoting antioxidative metabolite processing, and recovery. These findings provide a comprehensive description of OVX-induced glutathione redox stress at multiple levels and support HPL therapy as an effective modulator in renal tissues to locally influence the glutathione metabolism pathway and subsequent redox homeostasis.

Research on the mechanism of Chinese herbal medicine Radix Paeoniae Rubra in improving chronic pelvic inflammation disease by regulating PTGS2 in the arachidonic acid pathway.

Radix Paeoniae Rubra (RPR) is a traditional Chinese medicine with anti-inflammatory effects that has been used in chronic pelvic inflammation disease (CPID) therapy. However, research on the mechanism of RPR in CPID therapy is lacking. Here, we used a network pharmacology method to screen targets and found that the PTGS2 target in the arachidonic acid (AA) pathway was significantly related to CPID. Then, regarding the molecular mechanism, it was further confirmed that RPR may reduce the development of CPID by regulating the PTGS2 target. The CPID rat model was established by mixed bacterial infection. We verified the expression of PTGS2 by immunohistochemical analysis, western blotting assays to detect the expression of PTGS2 protein, and polymerase chain reaction detection of PTGS2 mRNA expression. It was observed that the PTGS2 target decreased significantly after RPR administration at different doses. It is suggested that RPR can reverse the abnormal expression of PTGS2 in CPID rats. We believe that RPR is effective in the treatment of CPID, and RPR can reduce the inflammatory symptoms of CPID by regulating the level of PTGS2 in the AA pathway.

The relationship between patterns of insulin secretion and risks of gestational diabetes mellitus.

OBJECTIVE: To evaluate patterns of insulin secretion in pregnancy and analyze the association between insulin patterns and risks of gestational diabetes mellitus (GDM). METHODS: A prospective study was conducted to collect and analyze pregnant women's materials from January 2015 to December 2018. Pregnant women were grouped according to results of 75-g oral glucose tolerance test at 24-28 weeks of pregnancy: normal glucose tolerance (NGT) and GDM. Insulin secretion patterns were based on the time of peak(s) and shape of insulin secretion curve. The relationship between insulin secretion patterns and pregnant outcomes was analyzed. RESULTS: A total of 2432 pregnant women met the inclusion criteria during the study period. Among them, 737 (30.3%) women were grouped as GDM and 1695 (69.7%) as NGT. Type I insulin secretion represented the early phase of insulin secretion (peak time at 30 or 60 minutes), while type II represented the delayed peak of insulin secretion (peak time at 120 or 180 minutes). Logistic regression analysis showed that type II insulin secretion was a risk factor of pre-eclampsia, large-for-gestational-age, and neonatal hypoglycemia. CONCLUSION: The delayed insulin peak is a useful marker for risk of GDM and adverse pregnant outcomes in women with GDM.

The association between dietary protein intake and esophageal cancer risk: a meta-analysis.

Several papers studied dietary protein intake as a potential influence factor for esophageal cancer, but their findings were inconsistent. Thus, this meta-analysis was performed to identify the effect of protein intake on esophageal cancer risk. Potential case-control studies or cohort studies from the databases of Embase, Web of Science and PubMed were searched. The strength of association was quantified by pooling odds ratio (OR) and 95% confidence interval (CI). In total, 11 articles involving 2537 cases and 11432 participants were included in this meta-analysis. As a result, dietary protein intake had non-significant association on esophageal cancer risk overall (pooled OR = 1.11, 95% CI = 0.88-1.40). Meanwhile, we obtained consistent results in the subgroups analyses by study design, protein type, geographic locations and number of cases. Interestingly, dietary protein intake could significantly increase the risk of esophageal squamous cell carcinoma (pooled OR = 1.29, 95% CI = 1.02-1.62), instead of other disease type. To sum up, dietary protein intake had no significant association with esophageal cancer risk in the overall analysis; but, protein intake may be associated with the risk of esophageal squamous cell carcinoma. While some limitations existed in the present paper, more studies with large sample size are warranted to further confirm this result.

Analysis on the prevalence of hemorrhagic fever with renal syndrome in Jiangxi Province from 2012 to 2017 / 中华疾病控制杂志

Objective To analyze the epidemiological characteristics of HFRS and rodent monitoring data in JiangXi province from 2012 to 2017, so as to provide scientific basis for controlling HFRS prevalence. Methods Descriptive epidemiological method was adopted to analyze the changes in time, region, and population morbidity of HFRS and rodent monitoring data from 2012 to 2017 in the province. Results From 2012 to 2017, there were 3 763 HFRS cases with 33 deaths reported in JiangXi province, the incidence was 1.38/100 000, the case fatality was 0.88%.The incidence in males was significantly higher than that in females( 2＝452.282, P<0.001).In the composition of occupation,the proprotion of farmers was decreased, while household workers, workers waiting for employment, students and other occupations were increased.There were two peaks in spring (from May to June) and winter (from November to January), and the winter peak was obviously higher than the spring peak. The average rat density at the two surveillance areas was 3.63%. Rattus norvegicus was predominant in residential areas and Apodemus agrarius was predominant in the wild.The six years on average index of rats with virus was 0.04. Conclusion The incidence of epidemic hemorrhagic fever in JiangXi Province generally showed an upward trend from 2012 to 2017, which suggest that we should continue to strengthen comprehensive prevention and control measures: rodent control in high-incidence areas, popularize vaccination and replenishment, and carry out health education for the whole population.

[Ruyi Jinhuang Plaster suppresses BPH by reducing the expressions of P38, JNK2, NF-кBP65 and STAT3 in the prostate tissue of rats].

OBJECTIVE: To investigate the effect of Ruyi Jinhuang Plaster (RJP) on testosterone propionate-induced BPH in the rat model and its action mechanisms. METHODS: Forty-eight SD male rats were randomly divided into six groups of equal number: normal control, BPH model control, finasteride, and high-, medium- and low-dose RJP. The BPH model was made in the latter five groups by hypodermic injection of testosterone propionate. From the first day of modeling, the rats of the normal control and BPH model control groups were treated with blank plasters and those of the high-, medium- and low-dose RJP groups with RJPs at 42.0, 21.0 and 10.5 cm2/kg applied to the dehaired area of the back, and those of the finasteride group by gavage of finasteride at 4.5 mg/kg, all once a day for 30 successive days. Then the prostates of the animals were harvested for observation of histopathological changes by HE staining, measurement of the areas of interstitial and epithelial cells and prostatic glandular cavity, and determination of the expressions of P38, JNK2, NF-кBP65 and STAT3 proteins in the prostate tissue by Western blot. RESULTS: Compared with the BPH model controls, the high-dose RJP group showed significantly decreased proliferation and area proportion of prostatic epithelial cells (P < 0.05), increased area proportion of the prostatic glandular cavity (P < 0.05), and reduced expressions of P38, p-P38, NF-кBP65, P-NF-кBP65, STAT3, P-STAT3 and JNK2 in the prostate tissue (P < 0.05); the medium-dose RJP group exhibited markedly down-regulated expressions of JNK2 and NF-кBP65 (P < 0.05) but an up-regulated level of p-JNK (P < 0.05); while the low-dose RJP group displayed a remarkably reduced expression of JNK2 (P < 0.05) but an elevated level of p-JNK (P < 0.05). CONCLUSIONS: RJP suppresses BPH in the model rat by down-regulating the expressions of P38, p-P38, NF-кBP65, P-NF-кBP65, STAT3, P-STAT3 and JNK2 or up-regulating that of p-JNK in the prostate tissue.