Highlights • NGF induced long lasting mechanical sensitization in masseter muscle in rats. • NGF-induced mechanical sensitization was greater in female than male rats. • APV reversed NGF-induced ...mechanical sensitization in male but not female rats. • NGF increased NMDA expression in masseter nociceptors in both sexes. • NMDA expression in masseter nociceptors was similar between humans and rats.
A closer look at the mysterious HSD17B13 Dong, X. Charlie
Journal of lipid research,
November 2020, 2020-11-00, 20201101, Letnik:
61, Številka:
11
Journal Article
SUMMARY
The importance of low-frequency seismic data has been already recognized by geophysicists. However, there are still a number of obstacles that must be overcome for events recovery and noise ...suppression in low-frequency seismic data. The most difficult one is how to increase the signal-to-noise ratio (SNR) at low frequencies. Desert seismic data are a kind of typical low-frequency seismic data. In desert seismic data, the energy of low-frequency noise (including surface wave and random noise) is strong, which largely reduces the SNR of desert seismic data. Moreover, the low-frequency noise is non-stationary and non-Gaussian. In addition, compared with seismic data in other regions, the spectrum overlaps between effective signals and noise is more serious in desert seismic data. These all bring enormous difficulties to the denoising of desert seismic data and subsequent exploration work including geological structure interpretation and forecast of reservoir fluid. In order to solve this technological issue, feed-forward denoising convolutional neural networks (DnCNNs) are introduced into desert seismic data denoising. The local perception and weight sharing of DnCNNs make it very suitable for signal processing. However, this network is initially used to suppress Gaussian white noise in noisy image. For the sake of making DnCNNs suitable for desert seismic data denoising, comprehensive corrections including network parameter optimization and adaptive noise set construction are made to DnCNNs. On the one hand, through the optimization of denoising parameters, the most suitable network parameters (convolution kernel、patch size and network depth) for desert seismic denoising are selected; on the other hand, based on the judgement of high-order statistic, the low-frequency noise of processed desert seismic data is used to construct the adaptive noise set, so as to achieve the adaptive and automatic noise reduction. Several synthetic and actual data examples with different levels of noise demonstrate the effectiveness and robustness of the adaptive DnCNNs in suppressing low-frequency noise and preserving effective signals.
Forkhead transcription factors FoxO1/3/4 have pleiotrophic functions including anti-oxidative stress and metabolism. With regard to glucose metabolism, most studies have been focused on FoxO1. To ...further investigate their hepatic functions, we generated liver-specific FoxO1/3/4 knockout mice (LTKO) and examined their collective impacts on glucose homeostasis under physiological and pathological conditions. As compared to wild-type mice, LTKO mice had lower blood glucose levels under both fasting and non-fasting conditions and they manifested better glucose and pyruvate tolerance on regular chow diet. After challenged by a high-fat diet, wild-type mice developed type 2 diabetes, but LTKO mice remained euglycemic and insulin-sensitive. To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6) and Gck (glucokinase) in the FoxO-mediated glucose metabolism. Interestingly, ectopic expression of SIRT6 in the liver only reduced gluconeogenesis in wild-type but not LTKO mice whereas knockdown of Gck caused glucose intolerance in both wild-type and LTKO mice. The data suggest that both decreased gluconeogenesis and increased glycolysis may contribute to the overall glucose phenotype in the LTKO mice. Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Using a conjunction of Cluster in the mid‐altitude dayside magnetosphere and Swarm in the low‐altitude ionosphere, we show, by employing multi‐spacecraft analysis, that matched, strong magnetic ...perturbations and the corresponding mesoscale field‐aligned current (FAC) structures are measured in the high latitude polar cusp region during the 7 October 2015 storm. Two pairs of opposite (positive/negative) FACs are observed by both Cluster and Swarm, which may relate to pulsed magnetic reconnection at the dayside magnetopause. Furthermore, the current intensity of these matched FACs decreases from high to low latitude, consistent with the time elapsed since reconnection. Corresponding geomagnetic disturbances are also observed by ground stations. Our observations provide direct evidence for the coupling of mesoscale FACs between the magnetosphere, ionosphere and ground in the polar cusp region, where the signatures are driven in this case by conditions suitable for inducing reconnection.
Plain Language Summary
Field‐aligned currents (FACs) are the key medium for the interaction between the distant space magnetosphere (a region filled with Earth's magnetic field) and the near‐Earth space ionosphere. Magnetic reconnection is the most important process to transfer solar wind energy from dayside magnetosphere to nightside, which is accompanied by the generation of FACs extending from the high latitude region of the ionosphere to the magnetosphere. For such structures, extending across different space regions, joint observations by multiple spacecraft are necessary. Using simultaneous measurements of Cluster in the magnetosphere, Swarm in the ionosphere and geomagnetic stations on the ground, coordinated mesoscale FAC structures could show matched signatures in the magnetosphere and the ionosphere and the corresponding geomagnetic disturbances on the ground. Our observations provide direct evidence for the magnetosphere‐ionosphere‐ground coupling during the pulsed magnetic reconnection process.
Key Points
Multi‐spacecraft Cluster and Swarm reveal matched magnetic perturbation and corresponding mesoscale field‐aligned currents (FACs) at different altitudes in the cusp region
Multiple pairs of opposite FACs associated with pulsed magnetic reconnection are dominant currents system at the dayside during storm time
Direct evidence for detailed dayside mesoscale FACs coupling between magnetosphere, ionosphere and ground is provided
Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ...ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3' splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.
Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 ...(Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)-even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines-including excess follistatin (Fst)-that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.
Neuroendocrine prostate cancer (NEPC) has increasingly become a clinical challenge. The mechanisms by which neuroendocrine (NE) cells arises from prostate adenocarcinoma cells are poorly understood. ...FOXA1 is a transcription factor of the forkhead family that is required for prostate epithelial differentiation. In this study, we demonstrated that FOXA1 loss drives NE differentiation, demarcated by phenotypical changes and NEPC marker expressions. Mechanistically, this is mediated by FOXA1 binding to the promoter of interleukin 8 (IL-8), a chemokine previously shown elevated in NEPC, to directly inhibit its expression. Further, IL-8 upregulation activates the MAPK/ERK pathway, leading to ERK phosphorylation and enolase 2 (ENO2) expression. IL-8 knockdown or ERK inhibition, on the other hand, abolished FOXA1 loss-induced NE differentiation. Analysis of xenograft mouse models confirmed FOXA1 loss in NEPC tumors relative to its adenocarcinoma counterparts. Importantly, FOXA1 is downregulated in human NEPC tumors compared to primary and castration-resistant prostate cancers, and its expression is negatively correlated with that of ENO2. These findings indicate that FOXA1 transcriptionally suppresses IL-8, the expression of which would otherwise stimulate the MAPK/ERK pathway to promote NE differentiation of prostate cancer cells. Our data strongly suggest that FOXA1 loss may play a significant role in enabling prostate cancer progression to NEPC, whereas IL-8 and MAPK/ERK pathways may be promising targets for therapeutic intervention.
Abstract
We select the largest sample of Swift gamma-ray bursts (GRBs) so far to reexamine the classification in terms of time duration, hardness ratio, and physical collapse model. To analyze the ...sample selection effect, we divide the observed Swift GRB sample into four subsamples according to signal-to-noise level, spectral quality, and extended emission. First, we find that only the sample of Swift GRBs with well-measured peak energy can be evidently divided into two types at a boundary of ∼1 s, and other data sets are well described by three Gaussian functions. Using Swift GRBs with known redshift, a Kolmogorov–Smirnov test shows the intrinsic duration distributions of five data sets are equally distributed. Second, we ascertain in the plane of hardness ratio versus duration that the hardness ratio of short GRBs is significantly higher than those of middle classes and long GRBs, while the latter two components are the same in statistics, implying the so-called middle class to be artificial. Third, we apply a collapse model to discriminate the boundaries between collapse and noncollapse Swift bursts. It is interesting to find that a significant fraction, ≥30%, of Swift short GRBs could have originated from the collapsing progenitors, while all long GRBs are produced from the collapsars only. Finally, we point out that short GRBs with extended emission are the main contributors to the noncollapsar population with longer duration.
Our goal in this work was to illustrate the Epstein-Barr virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of ...nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV-encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The upregulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced upregulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers.
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