It is thought that KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity is disabled. Consequently, drugs targeting the inactive or guanosine ...5′-diphosphate–bound conformation are not expected to be effective. We describe a mechanism that enables such drugs to inhibit KRASG12C signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRASG12C is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine kinases enhanced KRASG12C inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRASG12C undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRASG12C-driven cancers.
In this paper, we consider spectral approximation of fractional differential equations (FDEs). A main ingredient of our approach is to define a new class of generalized Jacobi functions (GJFs), which ...is intrinsically related to fractional calculus and can serve as natural basis functions for properly designed spectral methods for FDEs. We establish spectral approximation results for these GJFs in weighted Sobolev spaces involving fractional derivatives. We construct efficient GJF-Petrov-Galerkin methods for a class of prototypical fractional initial value problems (FIVPs) and fractional boundary value problems (FBVPs) of general order, and we show that with an appropriate choice of the parameters in GJFs, the resulting linear systems are sparse and well-conditioned. Moreover, we derive error estimates with convergence rates only depending on the smoothness of data, so true spectral accuracy can be attained if the data are smooth enough. The ideas and results presented in this paper will be useful in dealing with more general FDEs involving Riemann-Liouville or Caputo fractional derivatives.
Under investigation in this paper is a coupled nonlinear Schrödinger (NLS) equation, which describes nonlinear pulse propagation in optical fibers by retaining terms up to the next leading asymptotic ...order. Based on the Lax pair of the coupled NLS equation, we construct the determinant representation of the N-fold Darboux transformation(DT). Furthermore, by using the obtained N-fold DT, we obtain its higher-order soliton, breather and rogue wave solutions. Finally, the dynamic characteristics of these solutions are discussed.
Alzheimer's disease (AD) is the most common type of dementia which characterized by a progressive loss of memory and cognitive function due to degeneration of synapses and axons. Currently, there is ...no cure for AD. Deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs) are two hallmark pathologic changes in the brains of Alzheimer's patients. Autophagy is the major mechanism in cells responsible for removing protein aggregates. Accumulation of immature autophagic vacuoles (AVs) in dystrophic neurites of Alzheimer patients' brains suggests that autophagy process is disrupted. Till now, it is far from clear what role autophagy plays in AD, a causative role, a protective role, or just a consequence of the disease process itself. To design more effective therapeutic strategies towards this devastating disorder, it is essential to understand the exact role of autophagy played during different stages of AD.
Magnetic nanomaterials were functionalized with dopamine hydrochloride as the functional reagent to afford a core–shell-type Fe
3
O
4
modified with polydopamine (Fe
3
O
4
@PDA) composite, which was ...used for the adsorption of cadmium ions from an aqueous solution. In addition, the effects of environmental factors on the adsorption capacity were investigated. Furthermore, the adsorption kinetics, isotherm, and thermodynamics of the adsorbents were discussed. Results revealed that the adsorption of cadmium by Fe
3
O
4
@PDA reaches equilibrium within 120 min, and kinetic fitting data are consistent with the pseudo-second-order kinetics (
R
2
> 0.999). The adsorption isotherm of Cd
2+
on Fe
3
O
4
@PDA was in agreement with the Freundlich model, with the maximum adsorption capacity of 21.58 mg/g. The thermodynamic parameters revealed that adsorption is inherently endothermic and spontaneous. Results obtained from the adsorption–desorption cycles revealed that Fe
3
O
4
@PDA exhibits ultra-high adsorption stability and reusability. Furthermore, the adsorbents were easily separated from water under an enhanced external magnetic field after adsorption due to the introduction of an iron-based core. Hence, this study demonstrates a promising magnetic nano-adsorbent for the effective removal of cadmium from cadmium-containing wastewater.
Graphical Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disease of the female reproductive system that seriously affects women's health. Berberine (BBR) has many pharmacological properties and is used ...as an insulin sensitizer. This study aimed to investigate the effect of BBR on PCOS and explore its related mechanisms.
Forty-two rats were randomly divided into the following six groups (n = 7 per group): control, control + BBR, PCOS-normal diet (ND), PCOS-ND + BBR, PCOS-high-fat diet (HFD), and PCOS-HFD + BBR. The PCOS rat models were established by injecting rats with dehydroepiandrosterone. Further, the rats were gavaged with BBR (150 mg/kg/d) for 6 weeks. Then, the body weight, HOMA-IR, and testosterone levels of all rats were determined. Cell apoptosis of ovary granulosa cells was determined by a TUNEL assay kit. Real-time quantification PCR (RT-qPCR) and western blotting were utilized to evaluate the expression of TLR4, LYN, PI3K, Akt, NF-kB, TNF-α, IL-1, IL-6, and caspase-3.
BBR reduced the levels of insulin resistance and testosterone in PCOS rats. Additionally, the cell apoptosis rate increased significantly in PCOS rats (P < 0.05) and decreased after BBR treatment (P < 0.05). The results of RT-qPCR and western blotting showed that the expression levels of TLR4, LYN, PI3K, Akt, NF-kB, TNF-α, IL-1, IL-6, and caspase-3 significantly increased in PCOS rats, while BBR suppressed their expression levels.
BBR may relieve PCOS pathology and IR values by inhibiting cell apoptosis and by regulating the expression levels of TLR4, LYN, PI3K, Akt, NF-kB, TNF-α, IL-1, IL-6, and caspase-3.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Colorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal ...cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.
Because of their exceptional capability to tailor the effective medium parameters, metamaterials have been widely used to control electromagnetic waves, which has led to the observation of many ...interesting phenomena, for example, negative refraction, invisibility cloaking, and anomalous reflections and transmissions. However, the studies of metamaterials or metasurfaces are mainly limited to their physical features; currently, there is a lack of viewpoints on metamaterials and metasurfaces from the information perspective. Here we propose to measure the information of a coding metasurface using Shannon entropy. We establish an analytical connection between the coding pattern of an arbitrary coding metasurface and its far-field pattern. We introduce geometrical entropy to describe the information of the coding pattern (or coding sequence) and physical entropy to describe the information of the far-field pattern of the metasurface. The coding metasurface is demonstrated to enhance the information in transmitting messages, and the amount of enhanced information can be manipulated by designing the coding pattern with different information entropies. The proposed concepts and entropy control method will be helpful in new information systems (for example, communication, radar and imaging) that are based on the coding metasurfaces.
Background and Purpose
Regulating P2X7 receptor‐mediated activation of NLRP3 inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process was ...modulated by gentiopicroside, the main active secoiridoid glycoside from Gentiana manshurica Kitagawa.
Experimental Approach
In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administered ethanol or using chronic plus binge ethanol feeding of Lieber‐DeCarli liquid diet to male C57BL/6 mice. In vitro, HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone marrow‐derived macrophages (BMDMs) were stimulated with LPS and ATP.
Key Results
In both the acute and chronic alcohol‐induced mouse hepatosteatosis models, gentiopicroside decreased serum aminotransferases and triglyceride accumulation. Up‐regulated SREBP1, down‐regulated PPARα and phosphorylated acetyl‐CoA carboxylase caused by acute and chronic alcohol feeding were modulated by gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 receptor‐NLRP3 activation by gentiopicroside inhibited IL‐1β production. In ethanol‐exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted lipid oxidation via activation of P2X7 receptor‐NLRP3 inflammasomes. Genetic or pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced SREBP1 expression in ethanol‐treated HepG2 cells. Gentiopicroside down‐regulated P2X7 receptor‐mediated inflammatory responses in LPS/ATP‐stimulated RAW 264.7 macrophages and BMDMs. IL‐1β from macrophages accelerated lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by gentiopicroside.
Conclusions and Implications
Activation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor‐NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.
Background and Aims
Trimethylation of Lys36 on histone 3 (H3K36me3) catalyzed by histone methyltransferase SET domain‐containing 2 (SETD2) is one of the most conserved epigenetic marks from yeast to ...mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor.
Approach and Results
Here, using a liver‐specific Setd2 depletion model, we found that Setd2 deficiency is sufficient to trigger spontaneous HCC. Meanwhile, Setd2 depletion significantly increased tumor and tumor size of a diethylnitrosamine‐induced HCC model. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also by regulating lipid metabolism in the liver. Setd2 deficiency down‐regulated H3K36me3 enrichment and expression of cholesterol efflux genes and caused lipid accumulation. High‐fat diet enhanced lipid accumulation and promoted the development of HCC in Setd2‐deficient mice. Chromatin immunoprecipitation sequencing analysis further revealed that Setd2 depletion induced c‐Jun/activator protein 1 (AP‐1) activation in the liver, which was trigged by accumulated lipid. c‐Jun acts as an oncogene in HCC and functions through inhibiting p53 in Setd2‐deficient cells.
Conclusions
We revealed the roles of Setd2 in HCC and the underlying mechanisms in regulating cholesterol homeostasis and c‐Jun/AP‐1 signaling.
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