Simultaneously expressed miR-424 and miR-381 synergistically suppress the proliferation and survival of renal cancer cells---Cdc2 activity is up-regulated by targeting WEE1

OBJECTIVES: MiRNAs are intrinsic RNAs that interfere with protein translation. Few studies on the synergistic effects of miRNAs have been reported. Both miR-424 and miR-381 have been individually reported to be involved in carcinogenesis. They share a common putative target, WEE1, which is described as an inhibitor of G2/M progression. Here, we studied the synergistic effects of miR-424 and miR-381 on renal cancer cells. METHODS: The viability of 786-O cells was analyzed after transfection with either a combination of miR-424 and miR-381 or each miRNA alone. We investigated cell cycle progression and apoptosis with flow cytometry. To confirm apoptosis and the abrogation of G2/M arrest, we determined the level of pHH3, which is an indicator of mitosis, and caspase-3/7 activity. The expression levels of WEE1, Cdc25, γH2AX, and Cdc2 were manipulated to investigate the roles of these proteins in the miRNA-induced anti-tumor effects. To verify that WEE1 was a direct target of both miR-424 and miR-381, we performed a dual luciferase reporter assay. RESULTS: We showed that the combination of these miRNAs synergistically inhibited proliferation, abrogated G2/M arrest, and induced apoptosis. This combination led to Cdc2 activation through WEE1 inhibition. This regulation was more effective when cells were treated with both miRNAs than with either miRNA alone, indicating synergy between these miRNAs. WEE1 was verified to be a direct target of each miRNA according to the luciferase reporter assay. CONCLUSIONS: These data clearly demonstrate that these two miRNAs might synergistically act as novel modulators of tumorigenesis by down-regulating WEE1 expression in renal cell cancer cells

An Unconventional Glutamatergic Circuit in the Retina Formed by vGluT3 Amacrine Cells

SummaryIn the vertebrate retina, glutamate is traditionally thought to be released only by photoreceptors and bipolar cells to transmit visual signals radially along parallel ON and OFF channels. Lateral interactions in the inner retina are mediated by amacrine cells, which are thought to be inhibitory neurons. Here, we report calcium-dependent glutamate release from vGluT3-expressing amacrine cells (GACs) in the mouse retina. GACs provide an excitatory glutamatergic input to ON-OFF and ON direction-selective ganglion cells (DSGCs) and a subpopulation of W3 ganglion cells, but not to starburst amacrine cells. GACs receive excitatory inputs from both ON and OFF channels, generate ON-OFF light responses with a medium-center, wide-surround receptive field structure, and directly regulate ganglion cell activity. The results reveal a functional glutamatergic circuit that mediates noncanonical excitatory interactions in the retina and probably plays a role in generating ON-OFF responses, crossover excitation, and lateral excitation

Novel albumin-binding multifunctional probe for synergistic enhancement of FL/MR dual-modal imaging and photothermal therapy

The fluorescence/magnetic resonance (FL/MR) dual-modal imaging could provide accurate tumor visualization to guide photothermal therapy (PTT) of cancer, which has attracted widespread attention from scientists. However, facile and effective strategies to synergistically enhance fluorescence intensity, MR contrast and photothermal efficacy have rarely been reported. This study presents a novel multifunctional probe Gd-EB-ICG (GI) for FL/MR dual-modal imaging-guided PTT of cancer. GIs can self-assemble with endogenous albumin to form drug-albumin complexes (GIAs), which exhibit excellent biocompatibility. Albumin can protect GIAs from the recognition and clearance by the mononuclear phagocytic system (MPS). High plasma concentration and long half-life allow GIAs to accumulate continuously in the tumor area through EPR effect and specific uptake of tumor. Because of the prolonged rotational correlation time (τR) of Gd chelates, GIAs exhibited superior MR contrast performance over GIs with more than 3 times enhancement of longitudinal relaxation efficiency (r1). The fluorescence quantum yield and photothermal conversion efficiency of GIAs was also significantly improved due to the constrained geometry, disrupted aggregation and enhanced photothermal stability. This simple and feasible strategy successfully resulted in a synergistic effect for FL/MR dual-modal imaging and photothermal therapy, which can cast a new light for the clinical translation of multifunctional probes

PHOTO-TRANSDUCTION MECHANISMS IN M2- AND M4-INTRINSICALLY PHOTOSENSITIVE RETINAL GANGLION CELLS

Non-image-forming vision in mammals is mediated primarily by melanopsin (OPN4)-expressing, intrinsically-photosensitive retinal ganglion cells (ipRGCs). In mouse M1-subtype ipRGCs, our laboratory has previously shown that melanopsin activates PLCβ4 (phospholipase C-β4) to open TRPC6,7 channels. Whether other ipRGC subtypes also adopt the same phototransduction mechanism still remains unknown. We have now examined mouse M2- and M4-cells. Surprisingly, we found a hitherto undescribed, melanopsin-driven ciliary phototransduction mechanism involving cyclic nucleotide as the second messenger in M2- and M4-ipRGCs. However, the last step of this phototransduction mechanism consists of the activation of an HCN (Hyperpolarization- and Cyclic-Nucleotide-gated) channel instead of a CNG (Cyclic-Nucleotide-Gated) channel as found in rods and cones and literally all other ciliary photoreceptors. The light-triggered generation of cyclic nucleotide in this rather unique pathway was verified by using a CNG (CNGA2) channel expressed heterologously via AAV2-virus in ipRGCs. Later experiments with photo-uncaging of caged-cyclic nucleotides has proven that the specific second messenger is cAMP, instead of cGMP as found for nearly all ciliary phototransduction mechanisms across the animal kingdom except jellyfish, which uses cAMP and is an evolutionarily ancient species. This second phototransduction pathway is also Gαq-subfamily-dependent. However, after knocking out Gαq-subfamily (Gαq, Gα11, and Gα14), the null-phenotype of the second pathway takes a longer time to develop than that of the M1-pathway. This suggests that the two pathways probably bifurcate at the G-protein step. Possibly, the second pathway is mediated by the Gβγ subunits that are coupled to Gαq-subfamily. The production of cAMP can arise from adenylyl cyclase activated directly by Gβγ subunits. Furthermore, we found that each M2-ipRGC has both the microvillous-motif PLC-mediated and the ciliary-motif cyclic-nucleotide-mediated pathways operating in parallel and synergistically. Our findings reveal a complex heterogeneity in phototransduction among ipRGCs and, more importantly, break a general dogma about segregation of the two phototransduction motifs. The co-existence of microvillous and ciliary phototransductions in a given cell, together with the involvement of cAMP instead of cGMP, may suggest that ipRGCs are extant ancestral photoreceptors in the animal kingdom

Transfer Learning Leveraging DPC Model for Thermal Energy Optimization in Residential Buildings

Previous researches into the building thermal energy optimization indicated that many DPC methods have great potentials in application to optimal control for the building thermal energy consumption. However, to ensure good performance for such DPC model, certain amount of data would be required to find a suitable thermal dynamic model for the building thermal dynamic behavior. Though the availability of sensors in buildings enables the large-scale data collection, data insufficiency for newly-built or pre-exist yet outdated buildings could still lead to the bad performance of the DPC models at early stage. Therefore, transfer learning is introduced in this project to obtain a DPC model for the thermal energy optimization of the residential buildings with limited data. To this end, we introduce a transfer learning scheme for building thermal dynamic modelling, which leverages source models from virtual buildings constructed through the BRCM toolbox and applies the ideas of the DPC models with proven good performance. A source domain modeling scheme based on virtual buildings for transfer learning of the building thermal dynamic model is introduced. The approach has great advantage in cost efficiency due to its independence of the physical construction and its efficiency in the data acquisition. Among all the potential transfer learning methods, we mainly look into the ICNN-based transfer learning scheme. To apply such method, the ICNN source models are to be trained based on properly processed source domain data. A target domain ICNN model are then obtained for the target building from the source domain models and limited target doamin data through transfer learning. The methods are implemented with data from real-life building units (from NEST, D¨ ubendorf) as the target domain data. The accuracy results of the transfer learning approaches are tested and evaluated

A numerical-analysis-based optimization method for location selection for planning residential areas in grid transportation networks

China’s economy has been rapidly growing over the past few decades; however, increasingly more modern cities are facing problems caused by poor city planning, such as traffic networks, resource distribution and routine management. Optimization methods are urgently needed during city development. From location planning perspective, the residential area issue is discussed in this paper. Based on this issue, a numerical-analysis-based method is proposed for selecting proper residential areas in grid transportation networks. First, a grid layout is introduced to formalize a real traffic network. Furthermore, to guarantee its approximation, a considerable amount of data are obtained from real-world scenarios based on the shortest routes to demonstrate the problem of traffic jams. Then, a quantitative evaluation system is proposed, which quantitatively evaluates the specified location with the traffic flow distribution index, traffic congestion index and infrastructure convenience index. Each index reflects the attitude of citizens from a unique perspective, which affects the final location planning and selection. Finally, an analytic hierarchy process is designed to analyse all these indices together for a comprehensive analysis, and case studies and experiments are conducted to demonstrate the effectiveness of the proposed method. The generated residential location can be considered as a technical reference for further city planning and development decisions

Towards Scalable Kernel-Based Regularized System Identification

This paper proposes a methodology for scalable kernel-based regularized system identification based on indirect methods. It leverages stochastic trace estimation methods and an iterative solver such as LSQR for the efficient evaluation of hyperparameter selection criteria. It also uses a derivative-free optimization approach to hyperparameter estimation, which avoids the need for computing gradients or Hessians of the objective function. Moreover, the method is matrix-free, which means it only relies on a matrix-vector oracle and exploits fast routines for various structured matrix-vector products. Our preliminary numerical experiments indicate that the methodologygy scales significantly better than direct methods, especially when dealing with large datasets and slowly decaying impulse responses

Nano-SiO2-Modified Waterborne Acrylic Acid Resin Coating for Wood Wallboard

As one of the key products of the whole wood custom home, the study of environmental protection coating technology for wood wallboard has practical significance. Waterborne acrylic acid (WAA), as an important research object of environmentally friendly coatings, has been studied mainly in the area of modification. However, there is less research on its application to the field of wood wallboard. Herein, we developed a facile strategy to prepare WAA resin coatings with excellent performance using SiO2 nanoparticles as modifiers and explored the feasibility of wood wallboard. In this work, a simple mechanical compounding method was used to modify the WAA resin coatings by adding nano-SiO2, aiming to improve their physicochemical properties such as hardness and abrasion resistance while maintaining gloss. It was found that nano-SiO2 showed different effects on the viscosity, gloss, adhesion, and abrasion resistance of WAA resin coating. The combined performance results showed that the wood wallboard finishes exhibit excellent performance when the modifier nano-SiO2 was added at 1 wt% in the WAA resin coating. This present work shows that the nano-SiO2-modified WAA resin coating for wood wallboard has a broad application prospect

Cryptotanshinone alleviates lipopolysaccharide and cigarette smoke-induced chronic obstructive pulmonary disease in mice via the Keap1/Nrf2 axis

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity worldwide. Cigarette smoking, which leads to abnormalities in the airways or alveoli and persistent obstruction of the airway's flow, is a significant risk factor of COPD. Cryptotanshinone (CTS) is the active ingredient in Salvia miltiorrhiza (Danshen) and has many pharmacological properties including anti-inflammatory, antitumor, and antioxidant properties, but its impact on COPD is uncertain. In the present study, the potential effect of CTS on COPD was investigated in a modified COPD mice model induced with cigarette smoke (CS) and lipopolysaccharide (LPS) exposure. CTS significantly reversed the decline in lung function, emphysema, inflammatory cell infiltration, small airway remodeling, pulmonary pathological damage, and airway epithelial cell proliferation in CS- and LPS-exposed mice. Additionally, CTS decreased inflammatory cytokines such as tumor necrosis factor α (TNF α), interleukins IL-6 and IL-1β, and keratinocyte chemoattractant (KC), increased the activities of superoxide dismutase (SOD), Catalase (CAT) and L-Glutathione (GSH), and repressed the expression of protein hydrolases matrix metalloprotein (MMP)− 9 and − 12 in pulmonary tissue and bronchoalveolar lavage fluid (BALF). The protective effects of CTS were also observed in human bronchial epithelial cell line BEAS-2B simulated with cigarette smoke condensate (CSC) and LPS. Mechanistically, CTS can repress the protein level of Keap1, resulting to activation of erythroid 2-related factor (Nrf2), finally alleviating COPD. In summary, the present findings demonstrated that CTS dramatically ameliorates COPD induced by CS and LPS via activating Keap1/Nrf2 pathway

Hydrogenation of Carbon Dioxide to Methanol over Non-Noble Catalysts: A State-of-the-Art Review

The malignant environmental changes caused by the ever-increasing amount of anthropogenic CO2 emissions have been particularly prominent in recent years. To achieve carbon mitigation and carbon neutrality, CO2 hydrogenation to methanol is regarded as a promising and sustainable route. However, the development of catalysts with exceptional performance and the establishment of a clear structure–activity relationship remain formidable challenges. Considering the lack of a state-of-the-art review on the catalytic progress of CO2 hydrogenation to methanol over non-noble catalysts, we conducted a detailed review in terms of the thermodynamic analysis, catalytic development, and reaction mechanism. In this work, we mainly reviewed the latest research progress of different catalysts including Cu-based, In2O3-based, bimetallic, solid solution, and other catalysts. Meanwhile, we summarized the effects of the support materials, promoters, and preparation methods on the catalytic performance. In addition, we also summarized the possible reaction mechanisms of direct hydrogenation of CO2 to methanol. Overall, this work would be of importance for the researchers to obtain a comprehensive understanding of the design and development of efficient catalysts for CO2 hydrogenation to methanol