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Gland macrophages are primed for gland development and functions through interactions within their niche. However, the phenotype, ontogeny, and function of steady-state salivary gland (SG) macrophages remain unclear. We herein identified CD11c+ and CD11c− subsets among CD64+ macrophages in steady-state murine SGs. CD11c− macrophages were predominant in the SGs of embryonic and newborn mice and decreased with advancing age. CD11c+ macrophages were rarely detected in the embryonic period, but rapidly expanded after birth. CD11c+, but not CD11c−, macrophage numbers decreased in mice treated with a CCR2 antagonist, suggesting that CD11c+ macrophages accumulate from bone marrow-derived progenitors in a CCR2-dependent manner, whereas CD11c− macrophages were derived from embryonic progenitors in SGs. CD11c+ and CD11c− macrophages strongly expressed colony-stimulating factor (CSF)-1 receptor, the injection of an anti-CSF-1 receptor blocking antibody markedly reduced both subsets, and SGs strongly expressed CSF-1, indicating the dependency of SG resident macrophage development on CSF-1. The phagocytic activity of SG macrophages was extremely weak; however, the gene expression profile of SG macrophages indicated that SG macrophages regulate gland development and functions in SGs. These results suggest that SG CD11c+ and CD11c− macrophages are developed and instructed to perform SG-specific functions in steady-state SGs. [ABSTRACT FROM AUTHOR]

Heteroepitaxial oxide-based nanocomposite films possessing a variety of functional properties have attracted tremendous research interest. Here, self-assembled vertically aligned nanocomposite (Pr0.5Ba0.5MnO3)1-x:(CeO2)x (x = 0.2 and 0.5) films have been successfully grown on single-crystalline (001) (La,Sr)(Al,Ta)O3 substrates by the pulsed laser deposition technique. Self-assembling behavior of the nanocomposite films and atomic-scale interface structure between Pr0.5Ba0.5MnO3 matrix and CeO2 nanopillars have been investigated by advanced electron microscopy techniques. Two different orientation relationships, (001)[100]Pr0.5Ba0.5MnO3//(001)[1-10]CeO2 and (001)[100]Pr0.5Ba0.5MnO3//(110)[1-10]CeO2, form between Pr0.5Ba0.5MnO3 and CeO2 in the (Pr0.5Ba0.5MnO3)0.8:(CeO2)0.2 film along the film growth direction, which is essentially different from vertically aligned nanocomposite (Pr0.5Ba0.5MnO3)0.5:(CeO2)0.5 films having only (001)[100]Pr0.5Ba0.5MnO3//(001)[1-10]CeO2 orientation relationship. Both coherent and semi-coherent Pr0.5Ba0.5MnO3/CeO2 interface appear in the films. In contrast to semi-coherent interface with regular distribution of interfacial dislocations, interface reconstruction occurs at the coherent Pr0.5Ba0.5MnO3/CeO2 interface. Our findings indicate that epitaxial strain imposed by the concentration of CeO2 in the nanocomposite films affects the self-assembling behavior of the vertically aligned nanocomposite (Pr0.5Ba0.5MnO3)1-x:(CeO2)x films. [ABSTRACT FROM AUTHOR]

Editor's Note: this Article has been retracted; the Retraction Note is available at https://doi.org/10.1038/s41598-023-32251-x [ABSTRACT FROM AUTHOR]

Cadmium-incorporated Li2FeSiO4/C composites have been successfully synthesized by a solid-state reaction assisted with refluxing. The effect and mechanism of Cd-modification on the electrochemical performance of Li2FeSiO4/C were investigated in detail by X-ray powder diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, Raman spectra, transmission electron microscopy, positron annihilation lifetime spectroscopy and Doppler broadening spectrum, and electrochemical measurements. The results show that Cd not only exists in an amorphous state of CdO on the surface of LFS particles, but also enters into the crystal lattice of LFS. Positron annihilation lifetime spectroscopy and Doppler broadening spectrum analyses verify that Cd-incorporation increases the defect concentration and the electronic conductivity of LFS, thus improve the Li1-ion diffusion process. Furthermore, our electrochemical measurements verify that an appropriate amount of Cd-incorporation can achieve a satisfied electrochemical performance for LFS/C cathode material. [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy (DAPT) reduced stroke risk in high-risk transient ischemic attack (TIA) patients assessed by ABCD2 score. Patients with positive diffusion-weighted imaging (DWI) were identified as imaging-based high-risk. The present study aims to investigate whether DAPT could reduce stroke risk in TIA with DWI positive. The study enrolled TIA patients within 72 h of onset from the prospective TIA database of the First Affiliated Hospital of Zhengzhou University. The predictive outcome was ischemic stroke at 90-day. The relationship between DAPT and stroke was analyzed in a cox proportional hazards model. The Kaplan–Meier curves of TIA patients with DAPT and monotherapy were plotted. Total of 661 TIA patients were enrolled, 279 of whom were DWI positive and 281 used DAPT. The 90-day stroke risk was higher in patients used monotherapy than those used DAPT in TIA with positive DWI (23.7% vs. 13.4%, p = 0.029). DAPT was associated with reduced stroke risk in TIA patients with positive DWI (hazard ratio [HR] = 0.54; 95% confidence interval [CI], 0.30–0.97; p = 0.037). However, the benefit didn't exist in TIA patients with negative DWI (HR = 0.43; 95% CI, 0.14–1.33; p = 0.142). Early use of DAPT reduced stroke risk in TIA patients with positive DWI. [ABSTRACT FROM AUTHOR]

Polymers with reversible elongation upon cooling (EUC) and contraction upon heating (CUH) enabled applications in actuators, fasteners, dampers, grippers, swimmers, sealants, etc. With the current working temperature being limited to mainly above zero Celsius, applications for subzero Celsius environments are obstructed. In addition, current reversible actuation needs a constant tensile load, or for the best case, under zero tensile load. Reversible EUC and CUH under compressive load is almost impossible and has not been explored. In this work, a cis poly(1,4-butadiene) based system has been developed. Actuated below zero Celsius, 69% EUC occurred under a tensile load; and 6.2% EUC and 17.9% CUH occurred under 0.05 MPa compressive load. The reversible actuation was driven by both entropy and enthalpy, which was validated by a series of characterization tools. [ABSTRACT FROM AUTHOR]

Elucidation of the molecular mechanism related to the dedifferentiation and redifferentiation during tissue culture will be useful for optimizing regeneration system of tea plant. In this study, an integrated sRNAome and transcriptome analyses were carried out during phase changes of the stem explant culture. Among 198 miRNAs and 8001 predicted target genes, 178 differentially expressed miRNAs and 4264 potential targets were screened out from explants, primary calli, as well as regenerated roots and shoots. According to KEGG analysis of the potential targets, pathway of "aminoacyl-tRNA biosynthesis", "proteasome" and "glutathione metabolism" was of great significance during the dedifferentiation, and pathway of "porphyrin and chlorophyll metabolism", "mRNA surveillance pathway", "nucleotide excision repair" was indispensable for redifferentiation of the calli. Expression pattern of 12 miRNAs, including csn-micR390e, csn-miR156b-5p, csn-miR157d-5p, csn-miR156, csn-miR166a-3p, csn-miR166e, csn-miR167d, csn-miR393c-3p, csn-miR394, csn-miR396a-3p, csn-miR396 and csn-miR396e-3p, was validated by qRT-PCR among 57 differentially expressed phase-specific miRNAs. Validation also confirmed that regulatory module of csn-miR167d/ERF3, csn-miR156/SPB1, csn-miR166a-3p/ATHB15, csn-miR396/AIP15A, csn-miR157d-5p/GST and csn-miR393c-3p/ATG18b might play important roles in regulating the phase changes during tissue culture of stem explants. [ABSTRACT FROM AUTHOR]

Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development. The present study reports a hypoparathyroidism-associated mutation R59L that alters Drosophila Gcm (Gcm) protein stability, rendering it unstable, and hyperubiquitinated via the ubiquitin-proteasome system (UPS). GcmR59L interacts with the Slimb-based SCF complex and Protein Kinase C (PKC), which possibly plays a role in its phosphorylation, hence altering ubiquitination. Additionally, R59L causes reduced Gcm protein levels in a manner independent of the PEST domain signaling protein turnover. GcmR59L proteins bind DNA, functionally activate transcription, and induce glial cells, yet at a less efficient level. Finally, overexpression of either wild-type human Gcmb (hGcmb) or hGcmb carrying the conserved hypoparathyroidism mutation only slightly affects gliogenesis, indicating differential regulatory mechanisms in human and flies. Taken together, these findings demonstrate the significance of this disease-associated mutation in controlling Gcm protein stability via UPS, hence advance our understanding on how glial formation is regulated. [ABSTRACT FROM AUTHOR]

The accurate detection of leukocytes is the basis for the diagnosis of blood system diseases. However, diagnosing leukocyte disorders by doctors is time-consuming and requires extensive experience. Automated detection methods with high accuracy can improve detection efficiency and provide recommendations to inexperienced doctors. Current methods and instruments either fail to automate the identification process fully or have low performance and need suitable leukocyte data sets for further study. To improve the current status, we need to develop more intelligent strategies. This paper investigates fulfilling high-performance automatic detection for leukocytes using a deep learning-based method. We established a new dataset more suitable for leukocyte detection, containing 6273 images (8595 leukocytes) and considering nine common clinical interference factors. Based on the dataset, the performance evaluation of six mainstream detection models is carried out, and a more robust ensemble model is proposed. The mean of average precision (mAP) @IoU = 0.50:0.95 and mean of average recall (mAR)@IoU = 0.50:0.95 of the ensemble model on the test set are 0.853 and 0.922, respectively. The detection performance of poor-quality images is robust. For the first time, it is found that the ensemble model yields an accuracy of 98.84% for detecting incomplete leukocytes. In addition, we also compared the test results of different models and found multiple identical false detections of the models, then provided correct suggestions for the clinic. [ABSTRACT FROM AUTHOR]

A globally accurate many-body expansion potential energy surface is reported for HCS(X2A′) by fitting a wealth of accurate ab initio energies calculated at the multireference configuration interaction level using aug-cc-pVQZ and aug-cc-pV5Z basis sets via extrapolation to the complete basis set limit. The topographical features of the present potential energy surface are examined in detail and is in good agreement with the raw ab initio results, as well as other theoretical results available in literatures. By utilizing the potential energy surface of HCS(X2A′), the dynamic studies of the C(3P) + SH(X2Π) → H(2S) + CS(X1∑+) reaction has been carried out using quasi-classical trajectory method. [ABSTRACT FROM AUTHOR]

Graphene oxide (GO) is an emerging material for energy and environmental applications, but it has been primarily produced using chemical processes involving high energy consumption and hazardous chemicals. In this study, we reported a new bioelectrochemical method to produce GO from graphite under ambient conditions without chemical amendments, value-added organic compounds and high rate H2 were also produced. Compared with abiotic electrochemical electrolysis control, the microbial assisted graphite oxidation produced high rate of graphite oxide and graphene oxide (BEGO) sheets, CO2, and current at lower applied voltage. The resultant electrons are transferred to a biocathode, where H2 and organic compounds are produced by microbial reduction of protons and CO2, respectively, a process known as microbial electrosynthesis (MES). Pseudomonas is the dominant population on the anode, while abundant anaerobic solvent-producing bacteria Clostridium carboxidivorans is likely responsible for electrosynthesis on the cathode. Oxygen production through water electrolysis was not detected on the anode due to the presence of facultative and aerobic bacteria as O2 sinkers. This new method provides a sustainable route for producing graphene materials and renewable H2 at low cost, and it may stimulate a new area of research in MES. [ABSTRACT FROM AUTHOR]

Cucumber is an agriculturally and economically important vegetable crop worldwide. Fruit flesh thickness is an important trait for cucumber and also a central determinant of yield, yet little is known about the underlying mechanism of this trait. In this study, bulked segregant analysis (BSA) combined with specific length amplified fragment sequencing (SLAF-seq) was applied to finely map the gene that underlies fruit flesh thickness in cucumber. A 0.19-Mb-long quantitative trait locus on chromosome 2 controlling fruit flesh thickness (QTL fft2.1) was identified and further confirmed by simple sequence repeat (SSR) marker-based classical QTL mapping in 138 F2 individuals. Gene prediction of this 0.19-Mb region identified 20 genes. Quantitative RT-PCR revealed higher expression levels of Csa2 M058670.1 (SET domain protein-lysine methyltransferase) in D8 (thick fruit flesh parent) compared with that in XUE1 (thin fruit flesh parent) during fruit development. Sequence alignment analysis of Csa2M058670.1 from thick and thin fruit flesh cucumber lines revealed a 4-bp deletion mutation in the promoter region of this candidate gene, which may result in the loss of Csa2M058670.1 activation in thin fruit flesh lines. The data presented herein suggest that Csa2M058670.1 is a possible candidate gene for controlling flesh thickness in cucumber. [ABSTRACT FROM AUTHOR]

Breast cancer causes morbidity and mortality among women worldwide, despite much research illuminating the genetic basis of this disease. Anti-angiogenesis therapies have been widely studied, although the association between angiopoietin-2 (ANGPT2) single nucleotide polymorphisms (SNPs) and breast cancer subtypes remains unclear. This case–control study included 464 patients with malignant breast neoplasms and 539 cancer-free females. We explored the effects of ANGPT2 SNPs on the susceptibility for a malignant breast neoplasm in a Chinese Han population. Five ANGPT2 SNPs (rs2442598, rs734701, rs1823375, 11,137,037, and rs12674822) were analyzed using TaqMan SNP genotyping. Carriers of the variant GG allele of rs1823375 were less likely than wild-type carriers to be diagnosed with clinically staged breast cancer, while females with human epidermal growth factor receptor 2 (HER2)-enriched disease carrying the CG or the CG+GG genotype at rs1823375 were significantly less likely than CC genotype carriers to be of lymph node status N1–N3. We also found that the T-T-C-A-T ANGPT2 haplotype significantly increased the risk for developing a malignant breast neoplasm by 1.385-fold (95% CI: 1.025–1.871; p < 0.05). Our study is the first to document a correlation between ANGPT2 polymorphisms and the development and progression of a malignant breast neoplasm in females of Chinese Han ethnicity. [ABSTRACT FROM AUTHOR]

Dynamic oxygen vacancies play a significant role in memristive switching materials and memristors can be realized via well controlled doping. Based on this idea we deposite Nb2O5-NaNbO3 nanocomposite thin films on SrRuO3-buffered LaAlO3 substrates. Through the spontaneous phase separation and self-assembly growth, two phases form clear vertical heteroepitaxial nanostructures. The interfaces between niobium oxide and sodium niobate full of ion vacancies form the conductive channels. Alternative I-V behavior attributed to dynamic ion migration reveals the memristive switching mechanism under the external bias. We believe that this phenomenon has a great potential in future device applications. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

GPRC6A is proposed to regulate energy metabolism in mice, but in humans a KGKY polymorphism in the third intracellular loop (ICL3) is proposed to result in intracellular retention and loss-of-function. To test physiological importance of this human polymorphism in vivo, we performed targeted genomic humanization of mice by using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9) system to replace the RKLP sequence in the ICL3 of the GPRC6A mouse gene with the uniquely human KGKY sequence to create Gprc6a-KGKY-knockin mice. Knock-in of a human KGKY sequence resulted in a reduction in basal blood glucose levels and increased circulating serum insulin and FGF-21 concentrations. Gprc6a-KGKY-knockin mice demonstrated improved glucose tolerance, despite impaired insulin sensitivity and enhanced pyruvate-mediated gluconeogenesis. Liver transcriptome analysis of Gprc6a-KGKY-knockin mice identified alterations in glucose, glycogen and fat metabolism pathways. Thus, the uniquely human GPRC6A-KGKY variant appears to be a gain-of-function polymorphism that positively regulates energy metabolism in mice. [ABSTRACT FROM AUTHOR]

GPRC6A is a widely expressed G-protein coupled receptor that regulates energy metabolism. Global deletion of Gprc6a in mice is reported to result in a metabolic syndrome-like phenotype and conditional deletion of Gprc6a in pancreatic β-cell and skeletal muscle respectively impair insulin secretion and glucose uptake. In the current study, we explore the hepatic functions of GPRC6A by conditionally deleting Gprc6a in hepatocytes by cross breeding Alb-Cre and Gprc6aflox/flox mice to obtain Gprc6aLiver-cko mice. Gprc6aLiver-cko mice on a normal diet showed excessive hepatic fat accumulation and glycogen depletion. These mice also exhibit impaired glucose and pyruvate tolerance, but normal insulin sensitivity. Decreased circulating FGF-21 levels and FGF-21 message expression in the liver were found in Gprc6aLiver-cko mice. Hepatic transcriptome analysis identified alterations in multiple pathways regulating glucose, fat and glycogen metabolism in Gprc6aLiver-cko mice. Taken together, our studies suggest that GPRC6A directly regulates hepatic metabolism as well as regulates the production and release of FGF-21 to control systemic energy homeostasis. GPRC6A's unique regulation of β-cell, skeletal muscle and hepatic function may represent a new therapeutic target for treating disordered energy metabolism metabolic syndrome and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Identification of the associations between microRNA molecules and human diseases from large-scale heterogeneous biological data is an important step for understanding the pathogenesis of diseases in microRNA level. However, experimental verification of microRNA-disease associations is expensive and time-consuming. To overcome the drawbacks of conventional experimental methods, we presented a combinatorial prioritization algorithm to predict the microRNA-disease associations. Importantly, our method can be used to predict microRNAs (diseases) associated with the diseases (microRNAs) without the known associated microRNAs (diseases). The predictive performance of our proposed approach was evaluated and verified by the internal cross-validations and external independent validations based on standard association datasets. The results demonstrate that our proposed method achieves the impressive performance for predicting the microRNA-disease association with the Area Under receiver operation characteristic Curve (AUC), 86.93%, which is indeed outperform the previous prediction methods. Particularly, we observed that the ensemble-based method by integrating the predictions of multiple algorithms can give more reliable and robust prediction than the single algorithm, with the AUC score improved to 92.26%. We applied our combinatorial prioritization algorithm to lung neoplasms and breast neoplasms, and revealed their top 30 microRNA candidates, which are in consistent with the published literatures and databases. [ABSTRACT FROM AUTHOR]

Retraction Note: Wogonin reversed resistant human myelogenous leukemia cells via inhibiting Nrf2 signaling by Stat3/NF- B inactivation These authors contributed equally: Xuefen Xu and Xiaobo Zhang. Reference 1 Xu X, Zhang X, Zhang Y. Author Correction: Wogonin reversed resistant human myelogenous leukemia cells via inhibiting Nrf2 signaling by Stat3/NF- B inactivation. [Extracted from the article]

The rapid generation of various species and strains of laboratory animals using CRISPR/Cas9 technology has dramatically accelerated the interrogation of gene function in vivo. So far, the dominant approach for genotyping of genome-modified animals has been the T7E1 endonuclease cleavage assay. Here, we present a polyacrylamide gel electrophoresis-based (PAGE) method to genotype mice harboring different types of indel mutations. We developed 6 strains of genome-modified mice using CRISPR/Cas9 system, and utilized this approach to genotype mice from F0 to F2 generation, which included single and multiplexed genome-modified mice. We also determined the maximal detection sensitivity for detecting mosaic DNA using PAGE-based assay as 0.5%. We further applied PAGE-based genotyping approach to detect CRISPR/ Cas9-mediated on- and off-target effect in human 293T and induced pluripotent stem cells (iPSCs). Thus, PAGE-based genotyping approach meets the rapidly increasing demand for genotyping of the fast-growing number of genome-modified animals and human cell lines created using CRISPR/Cas9 system or other nuclease systems such as TALEN or ZFN. [ABSTRACT FROM AUTHOR]

T cell functional exhaustion during chronic hepatitis B virus (HBV) infection may contribute to the failed viral clearance; however, the underlying molecular mechanisms remain largely unknown. Here we demonstrate that jumonji domain-containing protein 6 (JMJD6) is a potential regulator of T cell proliferation during chronic HBV infection. The expression of JMJD6 was reduced in T lymphocytes in chronic hepatitis B (CHB) patients, and this reduction in JMJD6 expression was associated with impaired T cell proliferation. Moreover, silencing JMJD6 expression in primary human T cells impaired T cell proliferation. We found that JMJD6 promotes T cell proliferation by suppressing the mRNA expression of CDKN3. Furthermore, we have identified platelet derived growth factor-BB (PDGF-BB) as a regulator of JMJD6 expression. PDGF-BB downregulates JMJD6 expression and inhibits the proliferation of human primary T cells. Importantly, the expression levels of JMJD6 and PDGF-BB in lymphocytes from CHB patients were correlated with the degree of liver damage and the outcome of chronic HBV infection treatment. Our results demonstrate that PDGF-BB and JMJD6 regulate T cell function during chronic HBV infection and may provide insights for the treatment strategies for CHB patients. [ABSTRACT FROM AUTHOR]

To investigate a possible methodology of exploiting herbal medicine and design polytherapy for the treatment of non-alcoholic fatty liver disease (NAFLD), we have made use of Cichorium glandulosum Boiss et Huet (CG), a traditional Chinese herbal medicine that has been proven to be effective in treating hepatic diseases. Here, we report that the extract of CG effectively reduced lipid accumulation under conditions of lipid overloading in vivo and in vitro (in a rat high-fat diet model and a hepG2 cell model of free fatty acid treatment). CG extract also protected hepatocytes from injury and inflammation to aid its lipid-lowering properties (in a rat high-fat diet model and a L02 cell model of acetaminophen treatment). Serum chemistry analysis accompanied by in vitro drug screening confirmed that CG-4, CG-10 and CG-14 are the lipo-effective components of CG. Western blotting analysis revealed that these components can regulate key lipid targets at the molecular level, including CD36, FATP5 and PPAR-a, thus the lipid oxidation and lipid absorption pathways. Finally, we adopted the experimental design and statistical method to calculate the best combination proportion (CG-4: CG-10: CG-14=2.065: 1.782: 2.153) to optimize its therapeutic effect. [ABSTRACT FROM AUTHOR]

Growing evidence highlights an association between an imbalance in the composition and abundance of bacteria in the breast tissue (referred as microbial dysbiosis) and breast cancer in women. However, studies on the breast tissue microbiome have not been conducted in non-Hispanic Black (NHB) women. We investigated normal and breast cancer tissue microbiota from NHB and non-Hispanic White (NHW) women to identify distinct microbial signatures by race, stage, or tumor subtype. Using 16S rRNA gene sequencing, we observed that phylum Proteobacteria was most abundant in normal (n = 8), normal adjacent to tumor (normal pairs, n = 11), and breast tumors from NHB and NHW women (n = 64), with fewer Firmicutes, Bacteroidetes, and Actinobacteria. Breast tissues from NHB women had a higher abundance of genus Ralstonia compared to NHW tumors, which could explain a portion of the breast cancer racial disparities. Analysis of tumor subtype revealed enrichment of family Streptococcaceae in TNBC. A higher abundance of genus Bosea (phylum Proteobacteria) increased with stage. This is the first study to identify racial differences in the breast tissue microbiota between NHB and NHW women. Further studies on the breast cancer microbiome are necessary to help us understand risk, underlying mechanisms, and identify potential microbial targets. [ABSTRACT FROM AUTHOR]

Constitutive NF-E2-related factor 2 (Nrf2, NFE2L2) activation has been recently reported to play a pivotal role in enhancing cell survival and resistance to anticancer drugs in many tumors. Wogonin had strong reversal potency via reduction of Nrf2 mRNA in Adriamycin (ADR)-induced resistant human chronic myelogenous leukemia (CML) K562/A02, but the mechanism of reduction of Nrf2 mRNA was still unclear. In this study, we aimed to delineate the mechanism by which Wogonin suppressed transcription of Nrf2 in resistant CML cells and further evaluate the reversal effects of Wogonin on the established animal models. Data indicated that Wogonin suppressed transcription of Nrf2 by NF-κB inactivation. Wogonin inhibited the binding of p65 to Nrf2 by suppression of the κB-binding activity. Further research revealed the κB2 site was responsible for the decreased Nrf2 by Wogonin in resistant K562 cells. Furthermore, reduction of pY705-Stat3 was involved in inhibition of the binding of p65 to Nrf2 by Wogonin. In vivo, Wogonin potentiated the inhibitory effect of ADR on leukemia development by suppressing pY705-Stat3 and Nrf2 signaling. In summary, these results demonstrated Wogonin could combat chemoresistance effectively through inhibiting Nrf2 via Stat3/NF-κB signaling, and supported that Wogonin can be developed into an efficient natural sensitizer for resistant human myelogenous leukemia. [ABSTRACT FROM AUTHOR]

Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20's antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is a major global health burden. Functional exhaustion and numerical reduction of HBV-specific cytotoxic T lymphocytes (CTLs) in the liver and peripheral blood limit anti-HBV CTL activity in patients with chronic HBV infection (CHB). However, the ongoing anti-HBV CD8+ T cell responses in the lymphoid organs are largely unknown due to the infeasibility of obtaining lymphoid organs from CHB patients. Here we demonstrate that the percentage of HBV-specific CD8+ T cells is higher in the spleen of CHB patients than that from peripheral blood and liver. Although they do respond to TCR stimulation and produce IFNγ, the cells proliferate poorly. Furthermore, miR-720 expression is upregulated in HBV-specific CD8+ T cells. Overexpression of miR-720 in primary human CD8+ T cells inhibits TCR stimulation-induced proliferation. We also demonstrate that TGFβ sustains miR-720 upregulation after TCR stimulation, and blood TGFβ levels are associated with the outcome of type I interferon treatment of CHB patients. Thus, therapies targeting miR-720 may help restore impaired immunity in CHB patients. [ABSTRACT FROM AUTHOR]