Abstract
We did 194 epochs of simultaneous 2.25/8.60 GHz observations of XTE J1810−197 in 926 days shortly following its reactivation in 2018 with Shanghai Tian Ma Radio Telescope (TMRT). Although ...its integrated profiles changed with both time and frequency during this period, they could be classified into 12 types according to phase areas of active radiation components. After MJD 59015, XTE J1810−197 turned from the normal emission state into the spiky emission state that was manifesting as a series of bright narrow sub-pulse bursts at both 2.25 and 8.60 GHz. Due to its variable integrated profiles and unsteady rotations, we got the spin frequency
ν
and spin-frequency derivatives
ν
̇
with the piecewise fitting method. In addition, its long-term declining trend of
ν
was also obtained as
ν
̇
=
−
3.2
(
1
)
×
10
−
13
s
−2
with the linear fitting method based on our observations spanning a comparatively longer period. We found its flux densities went through three stages: sharp decrease, stabilization, and day-to-day fluctuations in our dual-frequency observations. Although the flux density showed different stages, XTE J1810−197 showed a relatively flat spectrum (
α
> –1) in most observations. Assuming an ideal dipole magnetic field as some previous research works, we obtained the emission heights of XTE J1810−197 were about 7.5(9) × 10
4
km and 2.38(7) × 10
4
km at 2.25 and 8.60 GHz, respectively. We also found that its emission heights would decrease rapidly with the degree of magnetic field twisting.
The development of opioid-induced analgesic tolerance and hyperalgesia is a clinical challenge for managing chronic pain. Adaptive changes in protein translation in the nervous system are thought to ...promote opioid tolerance and hyperalgesia; however, how opioids drive such changes remains elusive. Here, we report that mammalian target of rapamycin (mTOR), which governs most protein translation, was activated in rat spinal dorsal horn neurons after repeated intrathecal morphine injections. Activation was triggered through μ opioid receptor and mediated by intracellular PI3K/Akt. Spinal mTOR inhibition blocked both induction and maintenance of morphine tolerance and hyperalgesia, without affecting basal pain perception or locomotor functions. These effects were attributed to the attenuation of morphine-induced increases in translation initiation activity, nascent protein synthesis, and expression of some known key tolerance-associated proteins, including neuronal NOS (nNOS), in dorsal horn. Moreover, elevating spinal mTOR activity by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersensitivity, and increased spinal nNOS expression. Our findings implicate the μ opioid receptor-triggered PI3K/Akt/mTOR pathway in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia. These data suggest that mTOR inhibitors could be explored for prevention and/or reduction of opioid tolerance in chronic pain management.
Graphene oxide quantum dots (GOQDs) attract great attention for their unique properties and promising application potential. The difficulty in the formation of a confined structure, and the numerous ...and diverse oxygen‐containing functional groups results in a low emission yield to GOQDs. Here, GOQDs with a size of about 5 nm, exfoliated from carbon fibers by microwave irradiation, are detected and analyzed. The exfoliated GOQDs are deeply oxidized and induce large numbers of epoxy groups and ether bonds, but only a small amount of carbonyl groups and hydroxyl groups. The subdomains of sp2 clusters, involving epoxy groups and ether bonds, are responsible for the two strong photoluminescence emissions of GOQDs under different excitation wavelengths. Moreover, GOQDs tend to self‐assemble at the edges of their planes to form self‐assembly films (SAFs) with the evaporation of water. SAFs can further assemble into different 3D patterns with unique microstructures such as sponge bulk, sponge ball, microsheet, sisal, and schistose coral, which are what applications such as supercapacitors, cells, catalysts, and electrochemical sensors need. This method for preparation of GOQDs is easy, quick, and environmentally friendly, and this work may open up new research interests about GOQDs.
Graphene oxide quantum dots (GOQDs) exfoliated from carbon fibers by microwave irradiation involve large numbers of confined oxygen‐containing groups, epoxy groups, and ether bonds, which results in two separate photoluminescence centers. The plane structure of GOQDs with confined groups also leads to perfect self‐assembly behavior, first self‐assembling into films and further assembling into different 3D patterns with unique microstructures.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Dysregulated amino acid increases the risk for heart failure (HF) via unclear mechanisms. Here, we find that increased plasma tyrosine and phenylalanine levels are associated with HF. Increasing ...tyrosine or phenylalanine by high-tyrosine or high-phenylalanine chow feeding exacerbates HF phenotypes in transverse aortic constriction and isoproterenol infusion mice models. Knocking down phenylalanine dehydrogenase abolishes the effect of phenylalanine, indicating that phenylalanine functions by converting to tyrosine. Mechanistically, tyrosyl-tRNA synthetase (YARS) binds to ataxia telangiectasia and Rad3-related gene (ATR), catalyzes lysine tyrosylation (K-Tyr) of ATR, and activates the DNA damage response (DDR) in the nucleus. Increased tyrosine inhibits the nuclear localization of YARS, inhibits the ATR-mediated DDR, accumulates DNA damage, and elevates cardiomyocyte apoptosis. Enhancing ATR K-Tyr by overexpressing YARS, restricting tyrosine, or supplementing tyrosinol, a structural analog of tyrosine, promotes YARS nuclear localization and alleviates HF in mice. Our findings implicate facilitating YARS nuclear translocation as a potential preventive and/or interfering measure against HF.
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•Increased plasma tyrosine and phenylalanine levels worsen heart function•The tyrosine-YARS-ATR axis is critical for regulating cardiac DDR and heart failure•SIRT1 detyrosylates and inactivates ATR•Targeting tyrosine-YARS-ATR axis slows the progression of heart failure in mice
Zhao et al. report that increased plasma tyrosine concentration is associated with the onset of chronic heart failure (HF). Increased tyrosine decreases the nuclear localization of YARS, inhibits the ATR-mediated DNA damage response pathway, accumulates DNA damage, elevates cardiomyocyte apoptosis, and promotes HF development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that connects the Ca
-dependent signalling to multiple cellular responses. Calcineurin inhibitors (CNIs) have ...been widely used to suppress immune response in allograft patients. However, CNIs significantly increase cancer incidence in transplant recipients compared with the general population. Accumulating evidence suggests that CNIs may promote the malignant transformation of cancer cells in addition to its role in immunosuppression, but the underlying mechanisms remain poorly understood. Here, we show that calcineurin interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme that connects two key metabolic pathways of cells, glycolysis and the tricarboxylic acid cycle. Mitochondrial-localized calcineurin dephosphorylates PDHA1 at Ser232, Ser293 and Ser300, and thus enhances PDC enzymatic activity, remodels cellular glycolysis and oxidative phosphorylation, and suppresses cancer cell proliferation. Hypoxia attenuates mitochondrial translocation of calcineurin to promote PDC inactivation. Moreover, CNIs promote metabolic remodelling and the Warburg effect by blocking calcineurin-mediated PDC activation in cancer cells. Our findings indicate that calcineurin is a critical regulator of mitochondrial metabolism and suggest that CNIs may promote tumorigenesis through inhibition of the calcineurin-PDC pathway.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Opioids are the gold standard for pharmacological treatment of neuropathic pain, but their analgesic effects are unsatisfactory in part due to nerve injury-induced downregulation of opioid receptors ...in dorsal root ganglia (DRG) neurons. How nerve injury drives such downregulation remains elusive. DNA methyltransferase (DNMT)-triggered DNA methylation represses gene expression. We show here that blocking the nerve injury-induced increase in DRG DNMT3a (a de novo DNMT) rescued the expression of Oprm1 and Oprk1 mRNAs and their respective encoding mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) proteins in the injured DRG. Blocking this increase also prevented the nerve injury-induced increase in DNA methylation in the promoter and 5'-untranslated region of the Oprm1 gene in the injured DRG, restored morphine or loperamide (a peripheral acting MOR preferring agonist) analgesic effects, and attenuated the development of their analgesic tolerance under neuropathic pain conditions. Mimicking this increase reduced the expression of Oprm1 and Oprk1 mRNAs and their coding MOR and KOR in DRG and augmented MOR-gated neurotransmitter release from the primary afferents. Mechanistically, DNMT3a regulation of Oprm1 gene expression required the methyl-CpG-binding protein 1, MBD1, as MBD1 knockout resulted in the decreased binding of DNMT3a to the Oprm1 gene promoter and blocked the DNMT3a-triggered repression of Oprm1 gene expression in DRG neurons. These data suggest that DNMT3a is required for nerve injury-induced and MBD1-mediated epigenetic silencing of the MOR and KOR in the injured DRG. DNMT3a inhibition may serve as a promising adjuvant therapy for opioid use in neuropathic pain management.
Two thousand sixty‐four lung cancer cases and 5342 controls were evaluated in this International Lung Cancer Consortium (ILCCO) pooled analysis on estrogen‐related hormonal factors and lung cancer in ...Asian women. Random effect of study site and fixed effect of age, smoking status, comprehensive smoking index and family history of lung cancer were adjusted for in the multivariable logistic regression models. We found that late onset of menarche conferred elevated odds of lung cancer with adjusted odds ratio (OR) of 1.24 (95% confidence interval CI = 1.05, 1.45) for 17 years or older, compared to 14 years or younger. Late onset of menopause at 55 years old or older was associated with lung cancer with OR = 1.24 (95% CI = 1.02, 1.51). Nonnatural menopause was associated with an OR of 1.39 (95% CI = 1.13, 1.71). More live births showed reversed association with lung cancer (ORs of 5 or more live births: 0.71 (95% CI = 0.60, 0.84), compared to 0‐2 live births (Ptrend < 0.001). A later first child delivery seemed associated with an increased susceptibility: OR of 21 to 25 years old: 1.23 (95% CI = 1.06, 1.40), 26 or older: 1.27 (95% CI = 1.06, 1.52), Ptrend = .010). The use of oral contraceptives appeared to be protective with an OR of 0.69 (95% CI = 0.57, 0.83). Stronger for adenocarcinoma than squamous cell carcinoma, these relationships were not clearly modified by smoking status, probably because of lower prevalence of smoking. This is a first and largest pooling study of lung cancer among Asian women and the results suggested potential roles of hormone‐related pathways in the etiology of this disease.
What's new?
Evidence suggests a relationship between estrogen‐related hormones and lung cancer, but most of these studies have been done in European populations. Here, the authors built the largest ever female Asian lung cancer population, by pooling 6 epidemiological studies. They found a correlation between lung cancer risk and older age at menarche and menopause. On the other hand, having more children was associated with reduced risk of lung cancer, as was oral contraceptive use. Interestingly, these associations differ from those reported in Europeans, in particular the associations with childbirth and with age at menache.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Papillary renal cell carcinoma (PRCC) can be divided into type 1 (PRCC1) and type 2 (PRCC2) and PRCC2 share a more invasive phenotype and worse prognosis. This study aims to identify potential ...prognostic and therapeutic biomarkers in PRCC2.
A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes (DEGs) were screened and potential biomarkers were explored by using Kaplan-Meier method and cox regression analysis. Functional enrichment analysis was utilized to evaluate the potential biological functions. Tumor infiltrating immune cells were estimated by CIBERSORT algorithm. Ninety-two PRCC2 samples from Fudan University Shanghai Cancer Center were obtained, and immunostaining was performed to validate prognostic and therapeutic significance of the potential biomarker.
PRCC2 has worse overall survival and shares distinct molecular characteristics from PRCC1. There was significant higher expression level of Targeting protein for Xklp2 (TPX2) in PRCC2 compared with normal tissues. Higher expression level of TPX2 was significantly associated with worse overall survival in PRCC2 and kinesin family genes expression were found significantly elevated in high risk PRCC2. Abundance of tumor infiltrating M1 macrophage was significantly higher in PRCC2 and it was also associated with worse overall survival. In the FUSCC cohort, higher TPX2 expression was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%).
TPX2 was a prognostic and therapeutic biomarker in PRCC2. Higher abundance of tumor infiltrating M1 macrophage was significantly associated with worse overall survival in PRCC2. mTOR inhibitors may have good efficacy in patients with high-risk PRCC2.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Introduction
This study aimed to investigate whether maternal blood lipid levels during early pregnancy are associated with the occurrence of congenital heart disease (CHD) in their offspring.
...Material and methods
In this single‐center case–control study, mothers of offspring with CHD (n = 230) and without CHD (n = 381) were included. Maternal lipid levels were determined on fasting blood samples taken in the first trimester. Relevant demographic and clinical data were extracted from the medical records. Maternal lipid profile was compared between the two groups, and regression analysis was performed to evaluate the association between lipid profile and CHD risk in offspring.
Results
Compared with the control group, levels of triglyceride, apolipoprotein‐A1, and apolipoprotein‐B in early pregnancy were significantly higher in the CHD group. Multivariate analyses showed that triglyceride (odds ratio OR 2.46, 95% CI 1.62–3.73, p < 0.01), total/high‐density lipoprotein cholesterol (OR 2.10, 95% CI 1.07–4.13, p = 0.03), and apolipoprotein‐A1 (OR 2.73, 95% CI 1.16–6.40, p = 0.02) were positively associated with CHD risk in offspring.
Conclusions
Elevated maternal lipid profile was associated with increased risk of CHD in offspring.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, ...and insulin sensitivity in overweight/obese children.
We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits.
Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%).
Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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