ON1 is a novel genotype of human respiratory syncytial virus (HRSV) subtype A, in children with acute respiratory tract infections (ARTIs). However, there is not much data on the prevalence and ...clinical and molecular characterization in China.Our study is based on the children who had respiratory infections positive for RSV-A admitted by Gansu Provincial Maternity and Child-care Hospital in Lanzhou (northwestern China) during the last 7 epidemic seasons from 2010 to 2017.In our study, different strains of the novel RSV-A genotype ON1, first identified in Canada in December 2010, were first detected in Gansu Provincial Maternity and Child-care Hospital in August 2012 and then followed by an abrupt expansion in the number of ON1 variants in the beginning of 2014 and eventually replaced all other RSV-A strains from 2015 to 2017. ON1 is characterized by a 72-nt duplication in the C-terminal region of the highly variable attachment glycoprotein (G), predicted to lengthen the polypeptide with 24 amino acids, including a 23-aa duplication, which likely changes antigenicity. New N-glycosylation sites occurred within the 23-aa duplication and 24-aa insertion of the ON1 viruses in our study. Notably, RSV infections occurred later, but peaked sooner from the 2014/2015 to 2016/2017 epidemic seasons, compared with the previous 4 seasons.Our study concluded that genotype ON1 has caused larger outbreaks and became the predominate genotype for HRSV subgroup A in Lanzhou from 2013 to 2017, and became the sole genotype of RSV-A in 2015/2016 and 2016/2017. Our data indicate that northwest of China and the world will eventually be dominated by the ON1 RSV-A genotype, including the possibility for vaccine development. Based on trends seen in RSV-B BA genotype, which predominated for decades, there is a possibility to develop a vaccine for children in the next 10 years.
Single-cell technologies measure unique cellular signatures but are typically limited to a single modality. Computational approaches allow the fusion of diverse single-cell data types, but their ...efficacy is difficult to validate in the absence of authentic multi-omic measurements. To comprehensively assess the molecular phenotypes of single cells, we devised single-nucleus methylcytosine, chromatin accessibility, and transcriptome sequencing (snmCAT-seq) and applied it to postmortem human frontal cortex tissue. We developed a cross-validation approach using multi-modal information to validate fine-grained cell types and assessed the effectiveness of computational data fusion methods. Correlation analysis in individual cells revealed distinct relations between methylation and gene expression. Our integrative approach enabled joint analyses of the methylome, transcriptome, chromatin accessibility, and conformation for 63 human cortical cell types. We reconstructed regulatory lineages for cortical cell populations and found specific enrichment of genetic risk for neuropsychiatric traits, enabling the prediction of cell types that are associated with diseases.
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•Joint single-nucleus multi-omic profiling in human tissues•Assessment of computational data integration methods using multi-modal measurements•Diverse relationships between DNA methylation and gene expression in individual cells•Reconstruction of regulatory hierarchy for 63 human cortical cell populations
Single-cell profiling has enabled unbiased cell-type classification. Rigorous comparison of cell types defined by different modalities requires the joint measurement of multiple signatures in the same cell. Luo et al. have developed single-nucleus methylcytosine, chromatin accessibility, and transcriptome sequencing (snmCAT-seq) and applied it to categorize human brain cortical cell types.
Total flavonoid tablet from Anemarrhenae Rhizoma (Zhimu tablet), which was made of total polyphenol components extracted from the dried rhizome of Anemarrhena asphodeloides Bge. (Zhimu in Chinese), ...is a novel traditional Chinese medicine prescribed for the treatment of diabetes. Mangiferin (MF) and neomangiferin (NMF) are the two main components detected and determined in Zhimu tablet, accounting for 8.9% of the total weight of each tablet. In the present study, high performance liquid chromatography (HPLC) coupled with time-of-flight (TOF) tandem mass spectrometry (MS) was applied to characterize the metabolites of MF and NMF in rat plasmas collected at different time points after oral administration of Zhimu tablet at a dose of 3.63g/kg (corresponding to 270mg/kg MF). Accurate mass measurement was used to determine the elemental composition of metabolites and thus to confirm the proposed structures of identified metabolites. Time points of appearance of some metabolites, such as isomers, were also taken into account during the structure confirmation. A total of 21 potential metabolites were found in rat plasma at different time points, and the metabolic pathways in vivo were involved in hydrolysis, methylation, glucuronide conjugation, glycoside conjugation, sulphation, dehydration and isomerisation. Furthermore, a selective and accurate LC–MS assay method was developed and validated for the quantification of MF in plasma. Semi-quantification of main conjugated metabolites was also performed in order to describe the dynamic metabolism profiles of polyphenol components in Zhimu tablet. MF concentration in plasma reached 1.36±0.47μgmL−1 about 5.0h after oral administration of Zhimu tablet, which showed a 3.24- and 4.91-fold increase in plasma maximum concentration and area under the concentration-time curve (AUC) from 0 to 24h of MF compared with those for rats administered with free MF, respectively. The results indicated that the pharmacokinetic processes and bioavailability of MF in rats would be affected by other components in Zhimu tablet.
The potential contributions of CD8
+
memory stem T cells to anti-tumor immunity and immunotherapy responses in gastric cancer has not been demonstrated. We found that CD8
+
memory stem T cell ...frequencies were increased in the peripheral blood of gastric cancer patients compared to healthy donors and declined in frequency with disease progression. Despite minimal in vitro cytotoxic activity, the adoptive transfer of CD8
+
memory stem T cells into Rag1
−/−
tumor bearing mice enhanced tumor regression compared to CD8
+
central or effector memory T cell counterparts. This effect was associated with an increase in splenic, draining lymph node and tumor infiltrating CD8
+
T cell numbers and the development of an altered CD8
+
T cell phenotype not seen during homeostasis. GSK-3β inhibition is known to promote memory stem T cell accumulation by arresting effector T cell differentiation in vivo. Surprisingly however, GSK-3β inhibition conversely increased the cytotoxic capacity of CD8
+
memory stem T cells in vitro, and this was associated with the induction of effector T cell-associated effector proteins including FasL. Finally, FasL neutralization following GSK-3β inhibition directly attenuated the anti-tumoral capacity of CD8
+
memory stem T cells both in vitro and in vivo. Altogether, our findings identify the therapeutic potential of modulating CD8
+
memory stem T cells for improved anti-tumoral responses against gastric cancer.
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Four new pregnanes (1–4), including one 21-norpregnane (4), together with two known pregnanes (5 and 6), were isolated from the twigs and leaves of Strophanthus divaricatus. Their ...structures were elucidated on the basis of spectroscopic data analysis, ECD data, and X-ray crystallographic study. The cytotoxic activities of these pregnanes against two human cancer cell lines were evaluated.
Abstract Salidroside (SAL) is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea . A recent study has reported that SAL can efficiently decrease atherosclerotic plaque ...formation in low-density lipoprotein receptor-deficient mice. This study was to investigate the molecular mechanism of antiatherogenic effects of SAL. Given the importance of endothelial nitric oxide synthase (eNOS) in atherosclerosis, we sought to elucidate whether SAL could stimulate eNOS activation and also to explore its upstream signaling pathway. Six-week old apoE−/− male mice were fed a high-fat diet for 8 weeks and then were administered with SAL for another 8 weeks. SAL significantly improved endothelial function associated with increasing eNOS activation, thus reduced the atherosclerotic lesion area. SAL increased eNOS-Ser1177 phosphorylation and decreased eNOS-Thr495 phosphorylation, indicative of eNOS activation in endothelium. The aortic sinus lesions in SAL treated mice displayed reduced inflammation. SAL significantly activated AMP-activated protein kinase (AMPK). Both AMPK inhibitor and AMPK small interfering RNA (siRNA) abolished SAL-induced Akt-Ser473 and eNOS-Ser1177 phosphorylation. In contrast, LY294002, the PI3k/Akt pathway inhibitor, abolished SAL-induced phosphorylation and expression of eNOS. High performance liquid chromatography (HPLC) analysis revealed that SAL decreased cellular ATP content and increased the cellular AMP/ATP ratio, which was associated with the activation of AMPK. SAL was found to decrease the mitochondrial membrane potential (ΔΨm), which is a likely consequence of reduced ATP production. The action of SAL to reduce atherosclerotic lesion formation may at least be attributed to its effect on improving endothelial function by promoting nitric oxide (NO) production, which was associated with mitochondrial depolarization and subsequent activation of the AMPK/PI3K/Akt/eNOS pathway. Taken together, our data described the effects of SAL on mitochondria, which played critical roles in improving endothelial function in atherosclerosis.
The interaction between gastric epithelium and immune response plays key roles in
-associated pathology. We demonstrated a procolonization and proinflammation role of MMP-10 in
infection. MMP-10 is ...elevated in gastric mucosa and is produced by gastric epithelial cells synergistically induced by
and IL-22 via the ERK pathway. Human gastric MMP-10 was correlated with
colonization and the severity of gastritis, and mouse MMP-10 from non-BM-derived cells promoted bacteria colonization and inflammation.
colonization and inflammation were attenuated in IL-22
, MMP-10
, and IL-22
MMP-10
mice. MMP-10-associated inflammation is characterized by the influx of CD8
T cells, whose migration is induced via MMP-10-CXCL16 axis by gastric epithelial cells. Under the influence of MMP-10, Reg3a, E-cadherin, and zonula occludens-1 proteins decrease, resulting in impaired host defense and increased
colonization. Our results suggest that MMP-10 facilitates
persistence and promotes gastritis.
To accurately evaluate the influence of the actual tension and compression state and stress ratio at the deck-to-rib welding seam position on the fatigue life of a bridge deck, this paper establishes ...a coupled stress analysis model that considers the welding residual stress and vehicle stress. Taking the Jiangyin Bridge as an example, a qualitative analysis of the fatigue life under the vehicle load and residual stress field is carried out using the proposed method. A case analysis showed that when the residual tensile stress in the welding seam position is superimposed on the mainly tensile cyclic vehicle load stress, the longitudinal stress relaxation exceeds the peak vehicle load stress; significant longitudinal stress relaxation occurred, while the transverse stress relaxation is not significant. However, when the residual tensile stress is superimposed on the mainly compressive cyclic vehicle load stress, the relaxations of both the longitudinal and transverse stresses are not obvious. Compared with the stress state of the welding point under the action of only the vehicle stress, when the coupling effect of the residual stress and vehicle stress is considered, i.e., the loading condition, the fatigue stress state of the weld point has undergone an essential change under cyclic compressive stress, that is, the compressive stress state that does not require a fatigue check is changed to the tensile stress state. Although the fatigue state of the tensile stress cycle condition has not changed, the fatigue life is reduced by varying degrees under either the compressive or tensile condition.
To investigate the protective effects of L-carnitine (LC) on lipopolysaccharide (LPS) - injured mouse pulmonary microvascular endothelial cells (PMVECs) and its effects on autophagy and apoptosis.
...Cultured mouse PMVECs were divided into three groups: ① Control group, ② LPS group (10 μg/ml, 3, 6, 12, 24 h), ③ LPS (10 μg/ml, 24 h)+LC (2.5, 5.0, 10 μg/ml) (LPS+LC) group. PMVECs apoptosis was examined by Annexin V-FITC/PI double labeling method. Autophagosome was detected by immunofluorescence staining. Levels of autophagy-related protein LC3 and apoptosis-related protein caspase-3 were detected by Western blot. PMVECs viability was measured by CCK-8.
① Compared with the control group, LPS treatment inhibited the PMVECs viability significantly, whereas the apoptosis rate and the expression of autophagy protein LC3 II were markedly increased after LPS treatment for 6 h, 12 h and 24 h. ② Compared with LPS group (10 μg/ml, 24 h), the PMVECs viability, levels of autophagy protein LC3 II and caspase-3 protein expressi
Cervical cancer (CC) is recognized as the most common neoplasm in the female reproductive system worldwide. The lack of chemotherapeutic agents with outstanding effectiveness and safety severely ...compromises the anti-cipated prognosis of patients. Aloperine (ALO) is a natural quinolizidine alkaloid with marked anti-cancer effects on multiple malignancies as well as favorable activity in relieving inflammation, allergies and infection. However, its therapeutic efficacy and underlying mechanism in CC are still unclear. In the current study, MTT assay was employed to evaluate the viability of HeLa cells exposed to ALO to preliminarily estimate the effectiveness of ALO in CC. Then, the effects of ALO on the proliferation and apoptosis of HeLa cells were further investigated by plate colony formation and flow cytometry, respectively, while the migration and invasion of ALO-treated HeLa cells were evaluated using Transwell assay. Moreover, nude mice were subcutaneously inoculated with HeLa cells to demonstrate the anti-CC properties of ALO in vivo. The molecular mechanisms underlying these effects of ALO were evaluated by Western blot and immunohistochemical analysis. This study experimentally demonstrated that ALO inhibited the proliferation of HeLa cells via G2 phase cell cycle arrest. Simultaneously, ALO promoted an increase in the percentage of apoptotic HeLa cells by increasing the Bax/Bcl-2 ratio. Additionally, the migration and invasion of HeLa cells were attenuated by ALO treatment, which was considered to result from inhibition of epithelial-to-mesenchymal transition. For molecular mechanisms, the expression and activation of the IL-6-JAK1-STAT3 feedback loop were markedly suppressed by ALO treatment. This study indicated that ALO markedly suppresses the proliferation, migration and invasion and enhances the apoptosis of HeLa cells. In addition, these prominent anti-CC properties of ALO are associated with repression of the IL-6-JAK1-STAT3 feedback loop.
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