ABSTRACTBrown adipose tissue (BAT) is an exclusive tissue of nonshivering thermogenesis. It is fueled by lipids and glucose and involved in energy and metabolic homeostasis. Intrauterine exposure to ...hyperglycemia during gestational diabetes mellitus may result in abnormal fetal development and metabolic phenotypes in adulthood. However, whether intrauterine hyperglycemia influences the development of BAT is unknown. In this study, mouse embryos were exposed to the intrauterine hyperglycemia environment by injecting streptozocin into pregnant mice at 1 d post coitum (dpc). The structure of BAT was examined by hematoxylin and eosin staining and immunohistochemical analysis. The glucose uptake in BAT was measured in vivo by 18F‐fluoro‐2‐deoxyglucose–micro–positron emission tomography. The gene expression in BAT was determined by real‐time PCR, and the 5′‐C‐phosphate‐G‐3′ site‐specific methylation was quantitatively analyzed. Intrauterine hyperglycemia exposure resulted in the impaired structure of BAT and decreased glucose uptake function in BAT in adulthood. The expressions of the genes involved in thermogenesis and mitochondrial respiratory chain in BAT, such as Ucp1, Cox5b, and Elovl3, were down‐regulated by intrauterine hyperglycemia exposure at 18.5 dpc and at 16 wk of age. Furthermore, higher methylation levels of Ucp1, Cox5b, and Elovl3 were found in offspring of mothers with streptozotocin‐induced diabetes. Our results provide the evidence for enduring inhibitory effects of intrauterine hyperglycemia on BAT development in offspring. Intrauterine hyperglycemia is associated with increased DNA methylation of the BAT specific genes in offspring, which support an epigenetic involvement.—Yu, D.‐Q., Lv, P.‐P., Yan, Y.‐S., Xu, G.‐X., Sadhukhan, A., Dong, S., Shen, Y., Ren, J., Zhang, X.‐Y., Feng, C., Huang, Y.‐T., Tian, S., Zhou, Y., Cai, Y.‐T., Ming, Z.‐H., Ding, G.‐L., Zhu, H., Sheng, J.‐Z., Jin, M., Huang, H.‐F. Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue. FASEB J. 33, 5425–5439 (2019). www.fasebj.org
In recent years, mobile health (mHealth) has gained popularity. Yoga apps help users to exercise at home and improve their health. It is worth discussing how to give yogis a better experience and ...higher satisfaction to improve their willingness to keep using yoga apps. In this study, the Daily Yoga app was selected as the research object to explore important factors related to its user experience design and user satisfaction. Through a literature review and Delphi method composed of eight experts, this study put forward the important criteria framework of user experience design for the Daily Yoga app and then, used the DEMATEL (Decision Making and Trial Evaluation Laboratory)-based ANP (Analytic Network Process) method to determine the factors' importance order and the causal relationships among them. Finally, combined with the results of an importance-performance analysis of 16 real users, we discuss the improvement measures. The research results show that the yoga class is the most critical factor in the user experience design of the Daily Yoga app, the target plan is a factor that is in great need of improvement, and having an attractive interface can improve user experience. The evaluation model of the study can act as a reference for improving user experience with the Daily Yoga app, and can also be widely used in the process of user experience design, questionnaire production, and evaluation optimization of mHealth app and related applications.
In recent years, there has been an upsurge in the number of mini-games on mobile commerce platforms. The emerging gamification phenomenon of e-commerce still requires theory and investigation in ...order to supplement its explanation. This study aims to explore the intention of users to play games on mobile commerce platforms, as well as the influence of gamification mechanisms on users' purchase intentions on these platforms. From the perspective of perceived value theory, data from 1586 mobile commerce shoppers in China were collected and analyzed using a structural equation model. The results of the study found that utilitarian value, hedonic value, and social value are positively correlated with game use intention, while spending less time/energy also positively affects game use intention. These games are more attractive to women. The usage rate of games and the average monthly spending amount on a mobile commerce platform are both positively correlated with users’ purchase intentions on the platform.
•Mobile commerce users play mini-games because they gain fun with less time spending.•Gamification has a positive impact on the purchase intentions of users who access mobile commerce platforms.•Utilitarian, hedonic, and social value positively influence users to play games on mobile commerce platforms.•Mini-games on mobile commerce platforms are more attractive to women.
The crossbar structure of resistive random access memory (RRAM) is the most promising technology for the development of ultrahigh‐density devices for future nonvolatile memory. However, only a few ...studies have focused on the switching phenomenon of crossbar RRAM in detail. The main purpose of this study is to understand the formation and disruption of the conductive filament occurring at the crossbar center by real‐time transmission electron microscope observation. Core–shell Ni/NiO nanowires are utilized to form a cross‐structure, which restrict the position of the conductive filament to the crosscenter. A significant morphological change can be observed near the crossbar center, which results from the out‐diffusion and backfill of oxygen ions. Energy dispersive spectroscopy and electron energy loss spectroscopy demonstrate that the movement of the oxygen ions leads to the evolution of the conductive filament, followed by redox reactions. Moreover, the distinct reliability of the crossbar device is measured via ex situ experiments. In this work, the switching mechanism of the crossbar core–shell nanowire structure is beneficial to overcome the problem of nanoscale minimization. The experimental method shows high potential to fabricate high‐density RRAM devices, which can be applied to 3D stacked package technology and neuromorphic computing systems.
A crossbar memristor with core–shell Ni‐NiO nanowires can restrict the position of the conductive filament at the nanoscale crossbar point for application in neuromorphic computing systems. The dynamic observation of resistive switching behavior is conducted via in situ transmission electron microscopy. When undergoing resistive switching behavior, the movement of oxygen ions induces morphology changes in the RESET process.
Light‐harvesting and conversion ability is important to promote plant growth, and especially when resources are limited. A near‐infrared (NIR) nanophosphor embedded with mesoporous silica ...nanoparticles (MSN), ZnGa2O4:Cr3+,Sn4+ (ZGOCS), was developed and its optical properties were harnessed to enhance the photosynthetic ability of Brassica rapa spp. chinensis. The broad excitation of ZGOCS from the ultraviolet to the visible region allowed the conversion of extra light into near‐infrared light (650–800 nm) and thus promoted the dual photosystem via the Emerson effect. ZGOCS@MSN was spherical with a size of 65±10 nm and good dispersion. A light conversion ability of up to 75 % under different wavelengths was achieved. Moreover, the electron transfer rate of photosynthesis increased by 100 % with a suitable ZGOCS@MSN concentration. Plant and animal models were used to explore the effects of the nanophosphor. ZGOCS@MSN distribution was tracked by monitoring its NIR emission in plant and animal tissues, demonstrating that this nanophosphor can be potentially utilized in plant growth.
A near‐infrared nanophosphor, ZnGa2O4:Cr3+,Sn4+ (ZGOCS@MSN), with high light‐harvesting efficiency triggers the Emerson effect of the photosynthetic centers (PSI and PSII) to enhance photosynthesis. A suitable ZGOCS@MSN concentration increased the fresh weight and chlorophyll content of Brassica rapa ssp. chinensis and enhanced the electron transfer rate and its distribution in various plant parts.
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct ...disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
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•First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets
Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.
Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen ...receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models. In addition, recent studies reported that anti-androgen therapy shows preclinical efficacy in androgen-receptor (AR)-positive TNBC cells. Here we examined the effect of palbociclib in combination with an anti-androgen enzalutamide in TNBC cells.
MDA-MB-453, BT-549, MDA-MB-231 and MDA-MB-468 TNBC cell lines were used for in vitro studies. Protein expressions were assessed by Western blot analysis. Cytostatic effect was examined by MTT assay. Cell cycle and apoptosis were examined by flow cytometry.
Palbociclib showed inhibitory effect in RB-proficient TNBC cells, and enzalutamide inhibited cell viability in AR-positive TNBC cells. Enzalutamide treatment could enhance the palbociclib-induced cytostatic effect in AR-positive/RB-proficient TNBC cells. In addition, palbociclib-mediated G1 arrest in AR-positive/RB-proficient TNBC cells was attenuated by RB knockdown.
Our study provided a preclinical rationale in selecting patients who might have therapeutic benefit from combining CDK4/6 inhibitors with AR antagonists.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote ...tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
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•Cancer cells secrete succinate to promote TAM polarization and cancer metastasis•Cancer-cell-derived secreted succinate is related to reduction of SDH activity•SUCNR1-triggered PI3K-HIF-1α axis mediates TAM polarization and cancer metastasis•Serum succinate is elevated in patients with lung cancer and serves as a biomarker
We have shown that cancer cells secrete succinate into extracellular milieu, which mediates TAM polarization and promotes cancer metastasis. Succinate exerts its effects on TAM polarization and cancer metastasis via a specific membrane receptor, SUCNR1, which transmits signaling through the PI3K/HIF-1α pathway.
Temporal lobe epilepsy (TLE) leads to extensive degradation of the quality of life of patients. Glycyrrhizic acid (GA) has been reported to exert neuroprotective effects on status epilepticus. ...Herein, the current study set out to explore the functional mechanism of GA in TLE young rats. Firstly, TLE young rat models were established using the lithium chloride and pilocarpine regimen and then subjected to treatment with different doses of GA, miR‐194‐5p‐antagomir, or/and sh‐prostaglandin‐endoperoxide synthase 2 (PTGS2) to observe changes in iron content, glutathione and malondialdehyde levels, and GPX4 (glutathione peroxidase 4) and PTGS2 protein levels in the hippocampus. Neuronal injury and apoptosis were assessed through HE, Nissl, and TUNEL staining. Additionally, the expression patterns of miR‐194‐5p were detected. The binding site of miR‐194‐5p and PTGS2 was verified with a dual‐luciferase assay. Briefly, different doses of GA (20, 40, and 60 mg/kg) reduced the epileptic score, frequency, and duration in TLE young rats, along with reductions in iron content, lipid peroxidation, neuronal injury, and apoptosis in the hippocampus. Silencing of miR‐194‐5p partly annulled the action of GA on inhibiting ferroptosis and attenuating neuronal injury in TLE young rats. Additionally, PTGS2 was validated as a target of miR‐194‐5p. GA inhibited ferroptosis and ameliorated neuronal injury in TLE young rats via the miR‐194‐5p/PTGS2 axis. Overall, our findings indicated that GA exerts protective effects on TLE young rats against neuronal injury by inhibiting ferroptosis through the miR‐194‐5p/PTGS2 axis.
Acute hepatopancreatic necrosis disease (AHPND) is a severe, newly emergent penaeid shrimp disease caused by Vibrio parahaemolyticus that has already led to tremendous losses in the cultured shrimp ...industry. Until now, its disease-causing mechanism has remained unclear. Here we show that an AHPND-causing strain of V. parahaemolyticus contains a 70-kbp plasmid (pVA1) with a postsegregational killing system, and that the ability to cause disease is abolished by the natural absence or experimental deletion of the plasmid-encoded homologs of the Photorhabdus insect-related (Pir) toxins PirA and PirB. We determined the crystal structure of the V. parahaemolyticus PirA and PirB (PirA(vp) and PirB(vp)) proteins and found that the overall structural topology of PirA(vp)/PirB(vp) is very similar to that of the Bacillus Cry insecticidal toxin-like proteins, despite the low sequence identity (<10%). This structural similarity suggests that the putative PirAB(vp) heterodimer might emulate the functional domains of the Cry protein, and in particular its pore-forming activity. The gene organization of pVA1 further suggested that pirAB(vp) may be lost or acquired by horizontal gene transfer via transposition or homologous recombination.
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