Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene ...receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.
Neurogenesis, a highly orchestrated process, entails the transition from a pluripotent to neural state and involves neural progenitor cells (NPCs) and neuronal/glial subtypes. However, the precise ...epigenetic mechanisms underlying fate decision remain poorly understood. Here, we delete KDM6s (JMJD3 and/or UTX), the H3K27me3 demethylases, in human embryonic stem cells (hESCs) and show that their deletion does not impede NPC generation from hESCs. However, KDM6-deficient NPCs exhibit poor proliferation and a failure to differentiate into neurons and glia. Mechanistically, both JMJD3 and UTX are found to be enriched in gene loci essential for neural development in hNPCs, and KDM6 impairment leads to H3K27me3 accumulation and blockade of DNA accessibility at these genes. Interestingly, forced expression of neuron-specific chromatin remodelling BAF (nBAF) rescues the neuron/glia defect in KDM6-deficient NPCs despite H3K27me3 accumulation. Our findings uncover the differential requirement of KDM6s in specifying NPCs and neurons/glia and highlight the contribution of individual epigenetic regulators in fate decisions in a human development model.
Most current short-term load forecasting models have difficulty in simultaneously taking into account the time-series nature of load data, the non-linear characteristics, and the ineffectiveness of ...extracting potential high-dimensional features from historical series. To solve this problem, we propose a hybrid neural algorithm model (DPCL). In the DPCL, we use convolutional neural networks to obtain the high-dimensional spatial features of the phase space reconstruction of the load time series. Then, we combine the obtained high-dimensional spatial features with the external influence features extracted in the Pearson correlation analysis. Long and short-term memory networks retrieve Spatio-temporal features through the connection layer and obtain prediction results. In addition, there are problems of network gradient degradation and overfitting during the training process, We use an improved differential evolutionary algorithm to optimize the topology and time step of the hybrid neural network. We use the public dataset of a European utility and the loaded dataset of a Chinese mathematical competition as practical arithmetic examples. Experiments have higher prediction accuracy and faster prediction speed compared with other traditional algorithms.
Nitrogen metabolism is as sensitive to water stress as photosynthesis, but its role in plant under soil drying is not well understood. We hypothesized that the alterations in N metabolism could be ...related to the acclimation of photosynthesis to water stress. The features of photosynthesis and N metabolism in a japonica rice ‘Jiayou 5’ and an indica rice ‘Zhongzheyou 1’ were investigated under mild and moderate soil drying with a pot experiment. Soil drying increased non-photochemical quenching (NPQ) and reduced photon quantum efficiency of PSII and CO2 fixation in ‘Zhongzheyou 1’, whereas the effect was much slighter in ‘Jiayou 5’. Nevertheless, the photosynthetic rate of the two cultivars showed no significant difference between control and water stress. Soil drying increased nitrate reducing in leaves of ‘Zhongzheyou 1’, characterized by enhanced nitrate reductase (NR) activity and lowered nitrate content; whereas glutamate dehydrogenase (GDH), glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) were relative slightly affected. ‘Jiayou 5’ plants increased the accumulation of nitrate under soil drying, although its NR activity was increased. In addition, the activities of GDH, GOT and GPT were typically increased under soil drying. Besides, amino acids and soluble sugar were significantly increased under mild and moderate soil drying, respectively. The accumulation of nitrate, amino acid and sugar could serve as osmotica in ‘Jiayou 5’. The results reveal that N metabolism plays diverse roles in the photosynthetic acclimation of rice plants to soil drying.
•Soil drying increased nitrogen metabolism in rice.•Increased N metabolism improves photosynthetic acclimation to soil drying.•NO3− reduction contributes to energy dissipation under water stress.•N metabolism involves in osmoregulation in rice under water stress.
Task-oriented dialogue systems depend on dialogue state tracking to keep track of the intentions of users in the course of conversations. Recent studies in dialogue state tracking have achieved good ...performance, although the great majority of them do not consider slot correlation and just predict the value of every slot separately. In this work, we propose an efficient slot correlation learning network that can capture the correlations among slots as precisely as possible. Specifically, a BERT-base-uncased encoder is first applied to encode the dialogue context, slot names and their corresponding values. Second, we design a cross multi-head attention module to calculate and fuse attention among dialogue context embedding, slot name embedding and corresponding value embedding, which extracts relevant features and provides them to other components to fully catch the slot-specific information of every slot. Finally, a transformer encoder module is used to catch the correlations among slots. Experimental results on MultiWOZ 2.0, MultiWOZ 2.1, and MultiWOZ 2.4 datasets demonstrate the effectiveness of our approach with 55.14%, 57.22% and 76.93% joint goal accuracy, respectively, which achieves new state-of-the-art performance.
CuO/Cu
2
O nanowire arrays (NWAs) were prepared on a Cu foil substrate through a simple thermal process. The NWAs were then grafted with reduced graphene oxide (rGO) nanosheets
via
self-assembly. The ...combination of various characterization techniques including SEM, TEM, XRD, and XPS revealed the unique integration between CuO/Cu
2
O NWAs and umbrella-like rGO nanosheets. The CuO/Cu
2
O NWAs@rGO sample was found to be more active than bare CuO/Cu
2
O NWAs for the photocatalytic reduction of CO
2
under simulated solar light. The improved photocatalytic activity was attributed to the slow recombination of charge carriers and the efficient transfer of photo-generated electrons through rGO nanosheets.
Schematic illustration of plausible mechanism for the photoreduction of CO
2
with H
2
O over the CuO/Cu
2
O NWAs@rGO catalysts.
Display omitted
•An MBR with internal circulation was used to cultivate granular sludge.•Granular sludge was cultivated directly in this MBR in a continuous-flow mode.•The resulting granular sludge ...was characterized by multi methods.•Granular sludge remained stable for a long-term operation.•Essential factors to influence the granulation process were illustrated.
This research was conducted to cultivate granular sludge directly in a continuous-flow membrane bioreactor and explore the main factors influencing the granulation process. By establishing a suitable internal hydrodynamic circulation in a membrane bioreactor, granular sludge (GS) was successfully cultivated into mature granules with a compact structure and clear shape, in which extracellular polymeric substances played an important role in maintaining its integrity. The results showed that the main factors to determine the cultivation of GS included the total retention of sludge by the membrane module, the internal hydrodynamic circulation, and the entanglement of filamentous bacteria to sludge particles. Filamentous bacteria initiated a granulation process under the action of internal circulation, and maintained the stability of GS for a long period by wrapping biomass aggregates together. Even though filamentous bacteria were the major dominant microbial species in the bioreactor, the microbial community was richly biodiverse, and was responsible for the removal of organic pollutants and nutrients. Overall, the results demonstrated an alternative option for cultivating stable GS directly in a continuous-flow membrane bioreactor.
The vast majority of thyroid cancers show a good prognosis. However, the treatment of locally advanced thyroid cancer presents a huge problem. The wide application of targeted and immunotherapy in ...neoadjuvant therapy for locally advanced thyroid cancer has become a new therapeutic direction. This article summarizes the research on neoadjuvant chemotherapy, radiotherapy, and targeted therapy and immunotherapy related to various pathological types of thyroid cancer, with a focus on the recent advancements and thoughts on the application of targeted and immunotherapeutic drugs in neoadjuvant therapy. The results provide additional options for the clinical treatment of locally advanced thyroid cancer.
Abstract Full-colour-sorting metalens using few nanostructured layers have recently generated considerable interest as high-sensitivity colour image sensors because of their reliability and high ...resolution. Based on the guided mode resonance principle and propagation phase modulation, a full-colour-sorting metalens is designed, which can theoretically obtain any wavelength of light from the incident white light and realize arbitrary wavelength focusing with the same focal length in the visible range. Without the loss of generality, we propose a prototype of such metalens used for sorting blue, green and red light from the visible spectrum commonly used in practical applications. The maximum focussing efficiency is over 50% with a relatively high numerical aperture of 0.7. The proposed full-colour-sorting metalens can be used in many applications, such as colour mixing, colour holography, colour filtering, wavelength division multiplexing and so on.
Abstract
Broad-spectrum resistance has great values for crop breeding. However, its mechanisms are largely unknown. Here, we report the cloning of a maize
NLR
gene,
RppK
, for resistance against ...southern corn rust (SCR) and its cognate
Avr
gene,
AvrRppK
, from
Puccinia polysora
(the causal pathogen of SCR). The
AvrRppK
gene has no sequence variation in all examined isolates. It has high expression level during infection and can suppress pattern-triggered immunity (PTI). Further, the introgression of
RppK
into maize inbred lines and hybrids enhances resistance against multiple isolates of
P. polysora
, thereby increasing yield in the presence of SCR. Together, we show that
RppK
is involved in resistance against multiple
P. polysora
isolates and it can recognize AvrRppK, which is broadly distributed and conserved in
P. polysora
isolates.
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