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In order to solve the problem of difficult deployment of existing deep learning-based defect detection models in terminal equipment with limited computational capacity, a lightweight steel surface defect testing model LSKA-YOLOv8 was proposed based on the YOLOv8n target detection framework. The model uses KernelWarehouse Conv (KWConv) with lower computational volumes, which significantly reduces the required computational resources. By updating the traditional Feature Pyramid Network (FPN) structure to Bi-directional Feature Pyramid Network (BiFPN), enhance the capture of contextual information and reduce the number of parameters of the model. In addition, the Spatial Pyramid Pooling Fast (SPPF) module was replaced with a more accurate Receptive Field Block (RFB) module, expanding the model’s sensory field and improving characteristic representation. At the same time, the Large Separable Kernel Attention (LSKAttention) module was introduced in the detection head, effectively enhancing the understanding and capture of the target characteristics, thus significantly improving the overall detection performance. Experiments on the NEU-DET dataset showed that the average accuracy of LSKA-YOLO increased by 4.4% on the map@0.5 indicator compared to the benchmark model, while the number of parameters and calculations of the model decreased by 26.7% and 50%, respectively. Provides valuable references and practical applications for deployment of defect detection models on computing-resource-limited terminal devices.

Abstract Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.

In plasma transferred arc welding (PTAW), the weld pool temperature often fluctuates. The spray weld layer is prone to overheating, leading to adverse effect on its performance. This study investigated the influence of spray welding current on the weld pool temperature and in turn on the microstructure, microhardness and corrosion resistance of the PTAW-Ni layer on a steel substrate. Weld pool temperature increased with increasing spray welding current and varied along the welding gun path before reaching the steady state. With increasing pool temperature, more Fe diffused from the substrate into the spray weld layer, leading to a widened fusion zone, an increased dilution rate and a decreased microhardness. The spray weld layer has a dendritic microstructure. The dendrites have a higher Cr content, while the interdendritic regions have a higher Ni content. Increasing weld pool temperature increased diffusion, resulting in reduced enrichment of the Cr and Ni elements. The increase of Fe and decrease of Cr in the spray weld layer caused the decreasing corrosion resistance.

Semisolid injection molding is a novel and ideal process for manufacturing particle reinforced magnesium composites. The main purpose of this article is to reveal the wear mechanism of SiC/AZ91D composite prepared by this method. AZ91D Mg alloy and its composites reinforced with 1 % and 2.5 % SiC particles were manufactured by the semisolid injection molding method and their microstructure and wear behavior were investigated. The composites are composed of a Mg matrix, consisting of unmelted AZ91D particles distributed in a resolidified Mg base, and uniformly-dispersed SiC particles. The dry wear tests showed that adding SiC reinforcement increases the friction coefficient, enhances the wear resistance at the low loads of 5 N and 10 N, but reduces the wear resistance at the high load of 20 N. The dominant wear mechanism is abrasive wear, accompanied by small contributions from adhesive and oxidative wear.

Abstract In recent years, levitated particles of optical traps in vacuum have shown the enormous potential for precision sensor development and new physics exploration. However, the accuracy of the sensor is still hampered by the uncertainty of the calibration factor relating the detected signal to the absolute displacement of the trapped particle. In this paper, we suggest and experimentally demonstrate a novel calibration method for optical tweezers based on free-falling particles in vacuum, where the gravitational acceleration is introduced as an absolute reference. Our work provides a calibration protocol with a great certainty and traceability, which is significant in improving the accuracy of precision sensing based on levitated optomechanical systems.

The existing optimization scheduling of regional CCHP system does not take into account the different control objectives and response characteristics of each unit under multiple operating states in the whole operation domain, so it is difficult to achieve the unified traction control of multiple operation stages of multiple units. To this end, this paper proposes a unified traction control strategy for multi-state operation of regional CCHP system. Based on the different control objectives and response characteristics CCHP unit under multiple states, a two-layer traction control strategy of the regional CCHP system and unit was established. The upper level takes into account the different control objectives and response characteristics of each unit under different operating states, and optimizes the target operating state of each traction unit. The lower level realizes the efficient traction control of each unit under the target operating state based on the optimization decision results. Finally, a simulation example is designed to verify that this paper can effectively consider the different control objectives and response characteristics of CCHP unit under different operating states to achieve the optimal traction control.

Abstract Fungal cell walls undergo continual remodeling that generates β-1,3-glucan fragments as products of endo-glycosyl hydrolases (GHs), which can be recognized as pathogen-associated molecular patterns (PAMPs) and trigger plant immune responses. How fungal pathogens suppress those responses is often poorly understood. Here, we study mechanisms underlying the suppression of β-1,3-glucan-triggered plant immunity by the blast fungus Magnaporthe oryzae. We show that an exo-β-1,3-glucanase of the GH17 family, named Ebg1, is important for fungal cell wall integrity and virulence of M. oryzae. Ebg1 can hydrolyze β-1,3-glucan and laminarin into glucose, thus suppressing β-1,3-glucan-triggered plant immunity. However, in addition, Ebg1 seems to act as a PAMP, independent of its hydrolase activity. This Ebg1-induced immunity appears to be dampened by the secretion of an elongation factor 1 alpha protein (EF1α), which interacts and co-localizes with Ebg1 in the apoplast. Future work is needed to understand the mechanisms behind Ebg1-induced immunity and its suppression by EF1α.

Particle-reinforced Mg matrix composites possess excellent mechanical and physical properties. In this study, a new processing technique, semisolid injection molding, was employed to fabricate SiCp/AZ91D composites. The microstructure and mechanical properties of the as-molded composites were investigated. The SiC particles were found to be uniformly distributed in the metal matrix and no agglomeration was observed. The presence of small voids next to the SiC particles was observed. The microhardness of the composites decreases with the increase of SiC content, and initially decreases and then increases to a stable level with the increase of casting temperature. The 2.5 wt% SiCp/AZ91D composite has the highest tensile strength, up to 10% higher than AZ91D and 18% higher than the 1 wt% SiCp/AZ91D composite. A large number of small dimples and spherical voids, formed after unmelted Mg particles were pulled out of the matrix, were observed on the tensile fracture surface. This study demonstrates that semisolid injection molding is a valuable technique for the manufacture of particle-reinforced metal matrix composites.

The velocity field and temperature field are crucial for metal foams to be used as a heat exchanger, but they are difficult to obtain through physical experiments. In this work, the fluid flow behavior and heat transfer performance in open-cell metal foam were numerically studied. Porous 3D models with different porosities (55–75%) and pore sizes (250 μm, 550 μm, and 1000 μm) were created based on the porous structure manufactured by the Lost Carbonate Sintering method. A wide flow velocity range from 0.0001 m/s to 0.3 m/s, covering both laminar and turbulent flow regimes, is fully studied for the first time. Pressure drop, heat transfer coefficient, permeability, form drag coefficient, temperature and velocity distributions were calculated. The calculated results agree well with our previous experimental results, indicating that the model works well. The results showed that pressure drop increased with decreasing porosity and increasing pore size. Permeability increased and the form drag coefficient decreased with increasing porosity, and both increased with increasing pore size. The heat transfer coefficient increased with increasing velocity and porosity, whereas it slightly decreased with increasing pore size. The results also showed that at high velocity, only the metal foam close to the heat source contributes to heat dissipation.

Abstract Purpose Segmentation of liver vessels from CT images is indispensable prior to surgical planning and aroused a broad range of interest in the medical image analysis community. Due to the complex structure and low-contrast background, automatic liver vessel segmentation remains particularly challenging. Most of the related researches adopt FCN, U-net, and V-net variants as a backbone. However, these methods mainly focus on capturing multi-scale local features which may produce misclassified voxels due to the convolutional operator’s limited locality reception field. Methods We propose a robust end-to-end vessel segmentation network called Inductive BIased Multi-Head Attention Vessel Net(IBIMHAV-Net) by expanding swin transformer to 3D and employing an effective combination of convolution and self-attention. In practice, we introduce voxel-wise embedding rather than patch-wise embedding to locate precise liver vessel voxels and adopt multi-scale convolutional operators to gain local spatial information. On the other hand, we propose the inductive biased multi-head self-attention which learns inductively biased relative positional embedding from initialized absolute position embedding. Based on this, we can gain more reliable queries and key matrices. Results We conducted experiments on the 3DIRCADb dataset. The average dice and sensitivity of the four tested cases were 74.8 $$\%$$ % and 77.5 $$\%$$ % , which exceed the results of existing deep learning methods and improved graph cuts method. The Branches Detected(BD)/Tree-length Detected(TD) indexes also proved the global/local feature capture ability better than other methods. Conclusion The proposed model IBIMHAV-Net provides an automatic, accurate 3D liver vessel segmentation with an interleaved architecture that better utilizes both global and local spatial features in CT volumes. It can be further extended for other clinical data.

Abstract Background Although the executive pathways of senescence are known, the underlying control mechanisms are diverse and not fully understood, particularly how cancer cells avoid triggering senescence despite experiencing exacerbated stress conditions within the tumor microenvironment. Methods Mass spectrometry (MS)-based proteomic screening was used to identify differentially regulated genes in serum-starved hepatocellular carcinoma cells and RNAi employed to determine knockdown phenotypes of prioritized genes. Thereafter, gene function was investigated using cell proliferation assays (colony-formation, CCK-8, Edu incorporation and cell cycle) together with cellular senescence assays (SA-β-gal, SAHF and SASP). Gene overexpression and knockdown techniques were applied to examine mRNA and protein regulation in combination with luciferase reporter and proteasome degradation assays, respectively. Flow cytometry was applied to detect changes in cellular reactive oxygen species (ROS) and in vivo gene function examined using a xenograft model. Results Among the genes induced by serum deprivation, NIPSNAP1 was selected for investigation. Subsequent experiments revealed that NIPSNAP1 promotes cancer cell proliferation and inhibits P27-dependent induction of senescence via dual mechanisms. Firstly, NIPSNAP1 maintains the levels of c-Myc by sequestering the E3 ubiquitin ligase FBXL14 to prevent the proteasome-mediated turnover of c-Myc. Intriguingly, NIPSNAP1 levels are restrained by transcriptional repression mediated by c-Myc-Miz1, with repression lifted in response to serum withdrawal, thus identifying feedback regulation between NIPSNAP1 and c-Myc. Secondly, NIPSNAP1 was shown to modulate ROS levels by promoting interactions between the deacetylase SIRT3 and superoxide dismutase 2 (SOD2). Consequent activation of SOD2 serves to maintain cellular ROS levels below the critical levels required to induce cell cycle arrest and senescence. Importantly, the actions of NIPSNAP1 in promoting cancer cell proliferation and preventing senescence were recapitulated in vivo using xenograft models. Conclusions Together, these findings reveal NIPSNAP1 as an important mediator of c-Myc function and a negative regulator of cellular senescence. These findings also provide a theoretical basis for cancer therapy where targeting NIPSNAP1 invokes cellular senescence.

ABSTRACT: Ducks infected with duck circovirus (DuCV) show symptoms such as feather loss, growth retardation and low body weight in the flock. The virus induces immunosuppression and increases the prevalence of infection with other pathogens. However, most studies on duck circovirus were focused on coinfection, and fewer studies had been conducted on the pathogenicity of duck circovirus alone. The aim of the present study was to investigate the pathogenesis of DuCV-1 in experimentally infected specific pathogen-free ducks. In this study, we sequenced the whole genome of a strain of duck circovirus and identified the virus genotype as DuCV-1b. This strain of duck circovirus was named SDLH(OR567883). Animal pathogenicity experiments were then conducted, wherein specific pathogen-free ducks were infected by mucosal injection and abdominal injection. Infected ducks were sampled for 4 consecutive weeks after infection and showed symptoms of dwarfism. We further examined the replication of DuCV-1 in the ducks. The highest virus titers in the 2 infection groups were found in the liver and spleen, with different results for the different routes of infection. Pathological sections of duck organs were made and it was found that organs such as the liver and spleen were damaged by DuCV-1. In conclusion, our experimental results indicate that DuCV-1 can infect ducks individually and cause widespread organ damage in infected ducks.

Abstract Sestrins are a small gene family of pleiotropic factors whose actions promote cell adaptation to a range of stress conditions. In this report we disclose the selective role of Sestrin2 (SESN2) in dampening aerobic glycolysis to adapt to limiting glucose conditions. Removal of glucose from hepatocellular carcinoma (HCC) cells inhibits glycolysis associated with the downregulation of the rate-limiting glycolytic enzyme hexokinase 2 (HK2). Moreover, the accompanying upregulation of SESN2 through an NRF2/ATF4-dependent mechanism plays a direct role in HK2 regulation by destabilizing HK2 mRNA. We show SESN2 competes with insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) for binding with the 3′-UTR region of HK2 mRNA. Interactions between IGF2BP3 and HK2 mRNA result in their coalescence into stress granules via liquid-liquid phase separation (LLPS), a process which serves to stabilize HK2 mRNA. Conversely, the enhanced expression and cytoplasmic localization of SESN2 under glucose deprivation conditions favors the downregulation of HK2 levels via decreases in the half-life of HK2 mRNA. The resulting dampening of glucose uptake and glycolytic flux inhibits cell proliferation and protect cells from glucose starvation-induced apoptotic cell death. Collectively, our findings reveal an intrinsic survival mechanism allowing cancer cells to overcome chronic glucose shortages, also providing new mechanistic insights into SESN2 as an RNA-binding protein with a role in reprogramming of cancer cell metabolism.

High‐performance beam‐steering devices play a crucial role for optical wireless communication (OWC), which can meet the demand for increasing number of wireless mobile devices and emerging high‐speed multimedia applications. Conventional beam‐steering optical components like spatial light modulator and digital micromirror device are limited to realize a small steering angle (typ. several degrees), thus dramatically limits the spatial scope of OWC. Herein, a beam‐steering metadevice utilizing an ultracompact metasurface assisted with a spatial light modulator is presented, which can significantly increase the beam‐steering angle without at the cost of complicated optical setup like conventionally used angle magnifier. Based on the actively tunable beam‐steering metadevice, an intelligent bidirectional optical broadcasting communication system is designed and experimentally demonstrated, which exhibits nine broadcasting areas covering a large field‐of‐view of 20° × 20°, with user‐defined dynamic beam‐steering ability in each area, and each user has a data rate of 10 Gbps for both upstream and downstream transmission. The proposed metadevices can meet the demand of intelligent optical wireless communication which requires both high‐performance and low‐cost for practical purpose, under currently available technical architectures.

The Fourier transform between the time and frequency signals of light enables highly efficient band usage in optical communications. Analogously, the Fourier transform between the wavefield and wavevector distributions in the optical spatial diffraction is useful to understand the bandwidth considered in the diffraction simulations. In this work, we thoroughly investigate the numerical techniques for controlling the bandwidth in the design of computer-generated holography. The experiments reveal the effects of bandwidth control on both accuracy improvement of diffraction equations and suppression of higher hologram orders. A general formula for controlling the bandwidth directly using the spatial-frequency components is concluded.

Images captured in low illumination environments can affect people’s judgment of image information. To raise the visual effect of low illumination images and preserve the integrity of image information, this study proposes two algorithms. One is an image enhancement algorithm for low illumination, which combines the WASOBI image denoising method for deep denoising of images and adaptive gamma correction for brightness adjustment of images. The other is an image brightness equalization algorithm for uneven lighting. This algorithm divides the image according to the illumination area, and uses guided filtering and adaptive gamma correction to equalize the brightness of the image. The laboratory outcomes demonstrate that the proposed image enhancement algorithm can effectively reduce the noise level of the image and adjust the brightness of the image, and the algorithm has a certain degree of stability. The subjective evaluation score of the image processed using the brightness equalization algorithm is 4.7, indicating that the image has good visual effects. The objective evaluation results prove the capability of the equilibrium algorithm, and comparing to other algorithms, the algorithm has the shortest operation time, only 0.9452 seconds. Therefore, the enhancement algorithm and brightness equalization algorithm proposed in the article have certain application value.

Abstract As a cutting-edge field of artificial intelligence in education (AIEd) that depends on advanced computing technologies, AI performance prediction model is widely used to identify at-risk students that tend to fail, establish student-centered learning pathways, and optimize instructional design and development. A majority of the existing AI prediction models focus on the development and optimization of the accuracy of AI algorithms rather than applying AI models to provide student with in-time and continuous feedback and improve the students’ learning quality. To fill this gap, this research integrated an AI performance prediction model with learning analytics approaches with a goal to improve student learning effects in a collaborative learning context. Quasi-experimental research was conducted in an online engineering course to examine the differences of students’ collaborative learning effect with and without the support of the integrated approach. Results showed that the integrated approach increased student engagement, improved collaborative learning performances, and strengthen student satisfactions about learning. This research made contributions to proposing an integrated approach of AI models and learning analytics (LA) feedback and providing paradigmatic implications for future development of AI-driven learning analytics.

Abstract Objectives To explore pro‐inflammatory cytokines status in the tear fluid of patients with hyperuricemia and gout and its association with uric acid level. Methods A total of 58 control subjects, 58 hyperuricemia patients including 40 asymptomatic hyperuricemia and 18 gout participants were recruited in this study. For tear analysis, each patient's tears were collected using capillary action microcaps after stimulation. Tear uric acid levels were measured using chemiluminescence. Tear and serum interleukin‐1beta (IL‐1β) and tumor necrosis factor‐alpha (TNF‐α) levels were measured using enzyme‐linked immunosorbent assay. The correlation of serum and tear uric acid levels with IL‐1β and TNF‐α were determined. Results Tear uric acid levels were significantly higher in hyperuricemia group (98.2 ± 51.5 vs. 42.7 ± 24.0 µmol/L, p

Abstract Endo-β-mannanases are important enzymes for degrading lignocellulosic biomass to generate mannan, which has significant health effects as a prebiotic that promotes the development of gut microbiota. Here, a novel endo-β-mannanase belonging to glycoside hydrolase (GH) family 113 from Paenibacillus cineris (PcMan113) was cloned, expressed and characterized, as one of only a few reported GH113 family β-mannanases. Compared to other functionally and structurally characterized GH113 mannanases, recombinant PcMan113 showed a broader substrate spectrum and a better performance. Based on a structural homology model, the highly active mutant PcMT3 (F110E/N246Y) was obtained, with 4.60- and 5.53-fold increases of enzyme activity (towards KG) and catalytic efficiency (k cat/K m, against M5) compared with the WT enzyme, respectively. Furthermore, molecular dynamics (MD) simulations were conducted to precisely explore the differences of catalytic activity between WT and PcMT3, which revealed that PcMT3 has a less flexible conformation, as well as an enlarged substrate-binding channel with decreased steric hindrance and increased binding energy in substrate recognition. In conclusion, we obtained a highly active variant of PcMan113 with potential for commercial application in the manufacture of manno-oligosaccharides. Graphical Abstract

Abstract Background Mesenchymal stem cells (MSC)-based tissue engineered breast represent the visible future for breast reconstruction after mastectomy. However, autologous MSCs might not be appropriate for the large graft construction due to cell senescence during excessive cell expansion, thus hindering its further off-the-shelf application. The human umbilical cord mesenchymal stem cells (hUCMSCs) have been found to induce low immune response and can be easily stored, making them ideal for off-the-shelf tissue engineering application. Here, we explored the feasibility of using umbilical cord mesenchymal stem cells as tissue-engineered breast seed cells. Methods The allogenic hUCMSCs were injected into transplanted fat tissue with or without breast scaffolds as an alternative for breast tissue engineering in vivo, and its potential mechanism of angiogenesis in vitro was explored. Results Transplantation of hUCMSCs promoted proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) through paracrine mechanism by activating the integrin β1/ERK1/2/HIF-1α/VEGF-A signaling pathway. Histological examination of grafted fat revealed that the group which received hUCMSCs transplantation had more fat tissue [(93.60 ± 2.40) %] and fewer MAC2+CD206− M1 macrophages [(0.50 ± 0.47) cells/field] compared to the control group [fat tissue (45.42 ± 5.96) and macrophage cells/field (5.00 ± 2.23)]. Moreover, the hUCMSCs- labeled with a tracing dye differentiated into adipocytes and vascular endothelial cells in the adipose tissue. When applied to the tissue-engineered breast with a scaffold, the group treated with hUCMSCs had more adipose tissues and CD31+ cells than the control group. Conclusions These results demonstrate that allogeneic hUCMSCs promote the regeneration of adipose tissue and can be used to construct a tissue engineered breast.

Summary: Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.

The kidneys have a high level of Netrin-1 expression, which protects against some acute and chronic kidney disorders. However, it is yet unknown how Netrin-1 affects renal proximal tubule cells in diabetic nephropathy (DN) under pathological circumstances. Research has shown that autophagy protects the kidneys in animal models of renal disease. In this study, we looked at the probable autophagy regulation mechanism of Netrin-1 and its function in the pathogenesis of DN. We proved that in HK-2 cell, high blood sugar levels caused Netrin-1 to be downregulated, which then triggered the Akt/mTOR signaling pathway and enhanced cell death and actin cytoskeleton disruption. By adding Netrin-1 or an autophagy activator in vitro, these pathogenic alterations were reverted. Our results indicate that Netrin-1 stimulates autophagy by blocking the Akt/mTOR signaling pathway, which underlies high-glucose-induced malfunction of the renal proximal tubules. After HK-2 cells were incubated with Netrin-1 recombination protein and rapamycin under HG conditions for 24 h, the apoptosis was significantly reduced, as shown by the higher levels of Bcl-2, as well as lower levels of Bax and cleaved caspase-3 (P=0.012, Cohen’s d=0.489, Glass’s delta=0.23, Hedges’ g=0.641). This study reveals that targeting Netrin-1-related signaling has therapeutic potential for DN and advances our knowledge of the processes operating in renal proximal tubules in DN.

Abstract Glucose metabolism contributes to DNA damage response pathways by regulating chromatin remodeling, double‐strand break (DSB) repair, and redox homeostasis, although the underlying mechanisms are not fully established. Here, a previously uncharacterized long non‐coding RNA is revealed that is call Vanguard which acts to promote HMGB1‐dependent DNA repair in association with changes in global chromatin accessibility. Vanguard expression is maintained in cancer cells by SP1‐dependent transcription according to glucose availability and cellular adenosine triphosphate (ATP) levels. Vanguard promotes complex formation between HMGB1 and HDAC1, with the resulting deacetylation of HMGB1 serving to maintain its nuclear localization and DSB repair function. However, Vanguard downregulation under glucose limiting conditions promotes HMGB1 translocation from the nucleus, increasing DNA damage, and compromising cancer cell growth and viability. Moreover, Vanguard silencing increases the effectiveness of poly (ADP‐ribose) polymerase inhibitors against breast cancer cells with wild‐type breast cancer gene‐1 status, suggesting Vanguard as a potential therapeutic target.

Long noncoding RNAs (lncRNAs) undergo extensive alternative splicing, but little is known about isoform functions. A prior investigation of lncRNA RP11-369C8.1 reported that its splice variant TRMP suppressed p27 translation through PTBP1. Here we characterize a second major splice variant, TRMP-S (short variant), whose enforced loss promotes cancer cell-cycle arrest and p27-dependent entry into cellular senescence. Remarkably, despite sharing a single common exon with TRMP, TRMP-S restrains p27 expression through distinct mechanisms. First, TRMP-S stabilizes UHRF1 protein levels, an epigenetic inhibitor of p27, by promoting interactions between UHRF1 and its deubiquitinating enzyme USP7. Alternatively, binding interactions between TRMP-S and FUBP3 prevent p53 mRNA interactions with RPL26 ribosomal protein, the latter essential for promoting p53 translation with ensuing suppression of p53 translation limiting p27 expression. Significantly, as TRMP-S is itself transactivated by p53, this identifies negative feedback regulation between p53 and TRMP-S. Different splicing variants of the RP11-369C8.1 gene thereby exert distinct roles that converge on the homeostatic control of p27 expression, providing an important precedent for understanding the actions of alternatively spliced lncRNAs.

The direct C–H multifunctionalization of quinoxalin-2(1H)-ones via multicomponent reactions has attracted considerable interest due to their diverse biological activities and chemical profile. This review will focus on recent achievements. It mainly covers reaction methods for the simultaneous introduction of C–C bonds and C–RF/C/O/N/Cl/S/D bonds into quinoxalin-2(1H)-ones and their reaction mechanisms. Meanwhile, future developments of multi-component reactions of quinoxalin-2(1H)-ones are envisaged, such as the simultaneous construction of C–C and C–B/SI/P/F/I/SE bonds through multi-component reactions; the construction of fused ring and macrocyclic compounds; asymmetric synthesis; green chemistry; bionic structures and other fields. The aim is to enrich the methods for the reaction of quinoxalin-2(1H)-ones at the C3 position, which have rich applications in materials chemistry and pharmaceutical pharmacology.

The δ-generalized labeled multi-Bernoulli (δ-GLMB) filter is an efficient approach for multiobject tracking in case of high clutter density and low detection probability. However, the formulation of the original δ-GLMB filter requires that the birth δ-GLMB filtering density is known a priori. It is inapplicable for the birth object appearing from unknown positions. To address this problem, an adaptive δ-GLMB filter is proposed to detect and track the birth objects with unknown position information. This adaptive filter establishes the birth δ-GLMB filtering density by using measurements at previous three successive times. Simulation results indicate that the proposed adaptive δ-GLMB filter may efficiently detect and track the multiple objects with unknown positions. Simulation results also demonstrate that the proposed adaptive δ-GLMB filter performs better than the other existing adaptive filters.

This work proposes a marginal distribution multi-target Bayes filter with assignment of measurements to track multiple targets in the presence of an unknown and variable number of targets, clutter, and missed detections. Mathematically, the association of the measurements with either a target or clutter may be established by maximizing the joint likelihood function of the measurement partition, which leads to a two-dimensional assignment problem. By the introduction of detecting label, a handling approach for missed detections is also developed and is applied to the proposed filter. This filter greatly reduces the number of hypothesized targets or Gaussian terms by selecting the predicted probability density of a target or one of its multiple updated probability densities as its state distribution at each time step. Experimental results indicate that the proposed filter requires a less computational load than the existing filters and performs better than the efficient implementations of the δ-generalized labeled multi-Bernoulli filter for multi-target tracking at low and moderate clutter densities.

ObjectivePeripheral neuropathies (PNs) are a group of disorders that affect the peripheral nervous system. PN in gout has been scarcely described. This study is conducted to determine the prevalence and related risk factors of PN, as assessed by vibration perception threshold (VPT) in patients with gout.MethodsA total of 442 patients were included in the cross-sectional study. The VPT values were measured by using the Biothesiometer sensory quantitative tester on each patient. The VPT value of either limb higher than 15 V was considered abnormal and is considered to have PN. The univariate and multivariate logistic regression models were used to identify risk factors for PN in patients with gout.ResultsWe included 442 patients with gout, 97.5% men, 26.9% tophaceous gout, mean age 45.5 ± 15.2 years, and 7.4 ± 4.6 years of disease duration. The prevalence of PN in patients with gout was 11.1%. Patients in the abnormal VPT group were older, had a longer gout duration, and had significantly higher levels of waist circumference, waist-to-hip ratio, systolic blood pressure (SBP), and erythrocyte sedimentation rate (ESR), as compared to patients in the normal vibration group (P < 0.05). The univariate logistic regression analysis demonstrated that there was a significant association between abnormal VPT and age, duration of gout, SBP, C-reactive protein, ESR, presence of tophi, and estimated glomerular filtration rate (eGFR) in all the subjects (P < 0.05). The multivariate logistic regression analysis indicated that age (odds ratio, 1.094) and presence of tophi (odds ratio, 1.048) were independent risk factors for PN in patients with gout.ConclusionThe abnormal VPT was significantly correlated with age and presence of tophi in patients with gout and the VPT level may be useful as a screening tool for assessment of PN in gout.

The main aim of this research was to determine the physiological response of the submerged macrophyte Vallisneria natans (V. natans) to black water with a foul odor. V. natans was chosen as the experimental plant species to investigate the morphological response and ecophysiological adaptation methods in response to varying light depths and black-odorous water. V. natans was planted in tap water (D), two types of black-odorous water (E and F), and under three distinct light conditions (low light, medium light, and high light). In the high-light condition with black-odorous water (E), the biomass content of V. natans declined from 1.78 g on the 14th day to 1.49 g on the 28th day, demonstrating that the black-odorous water inhibited the growth of V. natans. Under the stress of black-odorous water, the chlorophyll content of V. natans increased greatly in the early period but reduced during the latter experimental period. However, on the 21st day, maximum chlorophyll content of 1.30 mg/g (E) and 1.18 mg/g (F) was observed. In addition, the malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) activity was monitored and reported under black-odorous water stress in V. natans. The experimental results of this work demonstrated conclusively that odorous black water exerts a certain stress on the physiological development of V. natans. Future research should incorporate the evaluation of several plant species and vary the process and environmental conditions to produce field-relevant, dependable results.

Aurora-A kinase is frequently over-expressed in tumours. Here, the authors show that it modulates the activity of lactate dehydrogenase B, resulting in enhanced glycolysis, bio-synthesis and tumour growth.

The use of photosensitive proteins has become a competitive solar energy solution, owing to its pollution-free nature, high conversion efficiency, and good biocompatibility. Bacteriorhodopsin (bR) is an important light-sensitive protein that is widely used in the fabrication of photoelectronic devices. However, research on the optimization and comparison of the immobilization techniques is lacking. In this study, in order to obtain bR films with a high energy conversion efficiency, three immobilization techniques, namely dropcasting, electrophoretic sedimentation, and Langmuir–Blodgett deposition, were used to fabricate films, and their topographical and photoelectrical characteristics were compared. All three immobilization techniques can transfer bR molecules to substrates, forming functional photosensitive bR films. The absorption of the bR films at 568 nm reached the highest value of 0.3 under the EPS technique. The peak photocurrent for the EPS technique reached 5.03 nA. In addition, the EPS technique has the highest efficiency factor of 13.46, indicating that it can generate the highest value of photocurrent under the same light conditions, owing to the improved orientation, and no significant decrease in the peak photocurrent was observed after three weeks, which indicates the stability of the photoelectric response. These results indicate that the EPS technique has a great potential for the photoelectrical device fabrication and solar-energy conversion.

Purpose: This study aims to determine vitamin D concentrations in the vitreous and serum, as well as the expression levels of NLRP3 inflammasome pathway in the vitreous of patients with proliferative diabetic retinopathy (PDR). In addition, we investigated the possible correlation between NLRP3 inflammasome levels and vitamin D concentrations.Methods: We obtained vitreous samples before vitrectomy from 55 PDR patients, 25 non-diabetic patients with idiopathic macular hole (IMH), and 10 non-proliferative diabetic retinopathy (NPDR) patients. We also collected serum samples from the same patients. Enzyme-linked immunosorbent assay (ELISA) was used to examine NLRP3 inflammasome pathway proteins, including NLRP3, caspase-1, IL-1β, and VEGF. In addition, vitamin D concentrations were analyzed in Roche Cobas 6000's module e601 platform using electrochemiluminescence immune assay.Results: The levels of NLRP3 inflammasome pathway and VEGF increased dramatically in PDR vitreous. However, vitamin D concentrations in vitreous and serum followed the opposite trend. Meanwhile, vitreous and serum vitamin D concentrations were significantly negatively correlated with vitreous NLRP3 expression in PDR patients. Moreover, serum and vitreous vitamin D concentrations were positively correlated and demonstrated discriminatory ability in DR. The subgroup analysis of PDR group revealed that eyes with tractional retinal detachment (TRD) had higher NLRP3 inflammasome pathway and VEGF levels but lower vitamin D concentrations. Conversely, eyes that received preoperative pan-retinal photocoagulation (PRP) exhibited lower levels of NLRP3 inflammasome pathway, but vitamin D concentrations were irrelevant to laser treatment.Conclusions: Our results demonstrate a strong correlation between increased NLRP3 inflammasome pathway and decreased vitamin D concentrations in the vitreous of PDR patients, which may be linked to PDR pathogenesis. In addition, vitamin D supplementation may play a key role in preventing, treating, and improving PDR prognosis due to its inhibitory impact on NLRP3 inflammasome pathway and VEGF.

Abstract Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress‐responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiration are revealed. DDIT3 is induced during glutamine deprivation to promote glycolysis and adenosine triphosphate production via suppression of the negative glycolytic regulator TIGAR. In concert, a proportion of the DDIT3 pool translocates to the mitochondria and suppresses oxidative phosphorylation through LONP1‐mediated down‐regulation of COQ9 and COX4. This in turn dampens the sustained levels of reactive oxygen species that follow glutamine withdrawal. Together these mechanisms constitute an adaptive survival mechanism permitting tumor cells to survive metabolic stress induced by glutamine starvation.

The inflammasomes are important mediators of protective immunity by promoting inflammatory cytokine production and cell death. Here the authors show that a lncRNA, Neat1, is mobilized by inflammasome-activating signals to promote the assembly of several inflammasome complexes and cytokine maturation to regulate inflammation.

TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.

The relationship between thyroid hormones and serum urate is unclear. Our aim is to analyze the correlation between uric acid and thyroid hormones in gout patients and to explore the effect and mechanism of triiodothyronine on liver uric acid production. Eighty men patients with gout were selected to analyze the correlation between blood urate and thyroid function-related hormone levels. Stepwise multiple linear regression was used to analyze factors affecting blood urate in patients with gout. Levels of urate in serum, liver, and cell culture supernatant were measured after triiodothyronine treatment. Purine levels (adenine, guanine, and hypoxanthine) were also measured. Expression levels of Period2 and nucleotide metabolism enzymes were analyzed after triiodothyronine treatment and Period2-shRNA lentivirus transduction. Chromatin immunoprecipitation was used to analyze the effects of triiodothyronine and thyroid hormone receptor-β on Period2 expression. The results showed that in patients FT3 influenced the serum urate level. Furthermore, urate level increased in mouse liver and cell culture supernatant following treatment with triiodothyronine. Purine levels in mouse liver increased, accompanied by upregulation of enzymes involved in nucleotide metabolism. These phenomena were reversed in Period2 knockout mice. Triiodothyronine promoted the binding of thyroid hormone receptor-β to the Period2 promoter and subsequent transcription of Period2. Triiodothyronine also enhanced nuclear expression of Sirt1, which synergistically enhanced Period2 expression. The study demonstrated that triiodothyronine is independently positively correlated with serum urate and liver uric acid production through Period2, providing novel insights into the purine metabolism underlying hyperuricemia/gout pathophysiology.

Epidemiological research has shown that elevated serum urate concentration is a risk factor for the development of kidney disease; however, the mechanisms underlying this process have not yet been elucidated. To examine the role of urate in the kidney, we used Wistar rats to functionally disrupt expression of urate oxidase (UOX) by using the CRISPR/Cas9 system. In comparison to wild-type (WT) rats, serum urate levels spontaneously and persistently increased in UOX-KO rats, without showing a significant decrease in survival rate. Architecture and function of the kidneys in UOX-KO rats were impaired. Injury to the kidney resulted in increased interstitial fibrosis, macrophage infiltration, increased expression of NLRP3 and IL-1β, and activation of multiple cell-signaling pathways associated with autophagy, such as AMPK, p38 MAPK, ERK and JNK pathways. Inhibition of autophagy with the PI3K inhibitor 3-MA abrogated the development of kidney damage and attenuated renal fibrosis, macrophage infiltration, and expression of NLRP3 and IL-1β in injured kidneys. In conclusion, the UOX-KO rat is a great model to study hyperuricemia-related diseases. Hyperuricemia-induced autophagy and NLRP3-dependent inflammation are critically involved in the development of renal damage and, therefore, highlight the inhibition of autophagy and inflammation in search of therapeutic strategies to treat uric acid nephropathy.

Steroid hormones that serve as vital compounds are necessary for the development and metabolism of a variety of organisms. The neverland (NVD) family genes encode the conserved Rieske-type oxygenases, which are accountable for the dehydrogenation during the synthesis and regulation of steroid hormones. However, the His-tagged NVD protein from Caenorhabditis elegans expresses as inclusion bodies in Escherichia coli BL21 (DE3). This bottleneck can be solved through refolding by urea or the introduction of a maltose-binding protein (MBP) tag at the N-terminus. Through further research on purification after the introduction of a MBP tag at the N-terminus, the CD measurement and fluorescence-based thermal shift assay indicated that MBP was favorable for the NVD proteins’ solubility and stability, which may be beneficial for the large-scale manufacture of NVD protein for further research. The structural model contained the Rieske [2Fe–2S] domain and non-heme iron-binding motif, which were similar to 3-ketosteroid 9 α-hydroxylase.

Abstract Metal–organic framework (MOF) membranes have received increasing attention as adsorbents, yet single phase MOF membranes have certain limitations, which frustrate their capacity performance. In this work a MOF composite membrane was successfully prepared by a facile and green strategy through reasonable design. At first, a defect-free ZIF-8 membrane was fabricated on an ionic liquid modified pencil bar by a solvothermal method. Then, a novel poly(ethylenglycol) functionalized ZIF-8 composite membrane (ZIF-8/PEG-NH2) was prepared through a flexible coordination-based post-synthetic modification strategy. We found that reaction time and temperature were two crucial factors for successfully fabricating well-defined ZIF-8/PEG-NH2 membrane. Besides, the adsorption of phenolic endocrine disruptors (e.g., 4-nonylphenol) on original ZIF-8 membrane and ZIF-8/PEG-NH2 membrane was investigated, and the good adsorption selectivity of ZIF-8/PEG-NH2 membrane towards 4-nonylphenol was demonstrated, with high adsorption capacity and fast adsorption dynamics. Excitingly, such ZIF-8/PEG-NH2 membrane was successfully employed for the selective detection of 4-nonylphenol from environmental water samples, demonstrating its great application potential in environmental monitoring.

Abstract Reprogramming of adult somatic cells into induced pluripotent stem cells holds great promise in clinical therapy. Increasing evidences have shown that p53 and its target genes play important roles in somatic cell reprogramming. In this study, we report that PHLDA3, a p53 target gene, functions as a blockage of iPSCs generation by activating the Akt-GSK3β pathway. Furthermore, PHLDA3 is found to be transcriptionally regulated by Oct4. These findings reveal that PHLDA3 acts as a new member of the regulatory network of somatic cell reprogramming.

Nucleoplasmic translocation of NPM1 is integral to nucleolar stress sensing. Here, the authors show that nucleolar oxidation is a general cellular stress response, and that oxidation-related glutathionylation of NPM1 triggers its translocation and facilitates p53 activation.

The data-intensive research paradigm calls for using educational and learning data to generate actionable insights and improve the instruction and learning quality. Although previous research designed and employed teaching analytics or learning analytics tools, few research had incorporated multiple data sources to assess the overall teaching and learning processes comprehensively. To address this gap, we proposed a teaching and learning analytics (TLA) tool that integrated multiple data sources from the instructor and students during educational process, leveraged multiple analytic methods to visualize results and provide supportive feedforward, with the goal to provide data-driven evidence for educational improvement. Mixed methods were conducted from quantitative and qualitative ways to examine the tool's effects on actual instruction and learning processes. Our results showed that the designed TLA tool with feedforward suggestions had positive effects on instruction, learning, and instructor-student interactions. Based on the results, this research proposed implications for TLA tool design and pedagogical strategies.

We have recently reported a TP53 (known as p53) regulated long noncoding RNA named TRINGS (Tp53-regulated inhibitor of necrosis under glucose starvation). With the aid of TRINGS, p53 was shown to prevent cancer cells against necroptosis under glucose starvation. Our findings suggest that p53 may act as an oncogenic player in metabolic reprogramming.

Cyclin D1 is a critical regulator of cell cycle progression and works at the G1 to S-phase transition. Here, we report the isolation and characterization of the novel c-Myc-regulated lncRNA LAST (LncRNA-Assisted Stabilization of Transcripts), which acts as a CCND1 mRNA stabilizer. Mechanistically, LAST was shown to cooperate with CNBP to bind to the 5′UTR of CCND1 mRNA to protect against possible nuclease targeting. In addition, data from CNBP RIP-seq and LAST RNA-seq showed that CCND1 mRNA might not be the only target of LAST and CNBP; three additional mRNAs were shown to be post-transcriptional targets of LAST and CNBP. In a xenograft model, depletion of LAST diminished and ectopic expression of LAST induced tumor formation, which are suggestive of its oncogenic function. We thus report a previously unknown lncRNA involved in the fine-tuned regulation of CCND1 mRNA stability, without which CCND1 exhibits, at most, partial expression.

Although camptothecin (CPT) has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that 131-113-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay, cAMP response element binding protein (CREB) knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA) significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA) was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa, Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa, Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis.

The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1α-overexpressing plasmid (pcDNA3-PGC-1α) for 48 h. In the diabetic rats, decreased PGC-1α expression was associated with increased mitochondrial ROS generation in the renal cortex, increased proteinuria, glomerular hypertrophy, and higher glomerular 8-OHdG (a biomarker for oxidative stress). In vitro, hyperglycemia induced the downregulation of PGC-1α, which led to increased DRP1 expression, increased mitochondrial fragmentation and damaged network structure. This was associated with an increase in ROS generation and mesangial cell hypertrophy. These pathological changes were reversed in vitro by the transfection of pcDNA3-PGC-1α. These data suggest that PGC-1α may protect DN via the inhibition of DRP1-mediated mitochondrial dynamic remodeling and ROS production. These findings may assist the development of novel therapeutic strategies for patients with DN.

BACKGROUND: p53 abnormality and aneuploidy often coexist in human tumors, and tetraploidy is considered as an intermediate between normal diploidy and aneuploidy. The purpose of this study was to investigate whether and how p53 influences the transformation from tetraploidy to aneuploidy. PRINCIPAL FINDINGS: Live cell imaging was performed to determine the fates and mitotic behaviors of several human and mouse tetraploid cells with different p53 status, and centrosome and spindle immunostaining was used to investigate centrosome behaviors. We found that p53 dominant-negative mutation, point mutation, or knockout led to a 2∼ 33-fold increase of multipolar mitosis in N/TERT1, 3T3 and mouse embryonic fibroblasts (MEFs), while mitotic entry and cell death were not significantly affected. In p53-/- tetraploid MEFs, the ability of centrosome clustering was compromised, while centrosome inactivation was not affected. Suppression of RhoA/ROCK activity by specific inhibitors in p53-/- tetraploid MEFs enhanced centrosome clustering, decreased multipolar mitosis from 38% to 20% and 16% for RhoA and ROCK, respectively, while expression of constitutively active RhoA in p53+/+ tetraploid 3T3 cells increased the frequency of multipolar mitosis from 15% to 35%. CONCLUSIONS: p53 could not prevent tetraploid cells entering mitosis or induce tetraploid cell death. However, p53 abnormality impaired centrosome clustering and lead to multipolar mitosis in tetraploid cells by modulating the RhoA/ROCK signaling pathway.